7H-pyrrolo[2,3-d]pyrimidine derivatives

ABSTRACT

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives of formula I 
                         
wherein the symbols and substituents are as defined in the description, to processes for the preparation thereof, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives—alone or in combination with one or more other pharmaceutically active compounds—for the preparation of pharmaceutical compositions for the treatment especially of a proliferative disease, such as a tumor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 10/485,747 filedon Feb. 3, 2004, now U.S. Pat. No. 7,244,729, which is an applicationunder 35 U.S.C. § 371 of PCT International Application No.PCT/EP02/08780, which has an International filing date of Aug. 6, 2002,and which designated United Kingdom Application Ser. No. 0119249.1,filed Aug. 7, 2001, as priority.

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives and toprocesses for the preparation thereof, to pharmaceutical compositionscomprising such derivatives and to the use of such derivatives—alone orin combination with one or more other pharmaceutically activecompounds—for the preparation of pharmaceutical compositions for thetreatment especially of a proliferative disease, such as a tumour.

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives offormula I

whereinR₁ and R₂ are each independently of the other hydrogen, unsubstituted orsubstituted alkyl or cycloalkyl, a heterocyclic radical bonded via aring carbon atom, or a radical of the formula R₄—Y—(C═Z)— wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radical, Yis either not present or lower alkyl and Z is oxygen, sulfur or imino,with the proviso that R₁ and R₂ are not both hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical;R₃ is a heterocyclic radical or an unsubstituted or substituted aromaticradical;G is C₁-C₇-alkylene, —C(═O)—, or C₁-C₆-alkylene-C(═O)— wherein thecarbonyl group is attached to the NR₁R₂ moiety;Q is —NH— or —O—, with the proviso that Q is —O— if G is —C(═O)— orC₁-C₆-alkylene-C(═O)—; andX is either not present or C₁-C₇-alkylene, with the proviso that aheterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;or a salt of the said compounds.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Where compounds of formula I are mentioned which can form tautomers, itis meant to include also the tautomers of such compounds of formula I.In particular, tautomerism occurs e.g. for compounds of formula I whichcontain a 2-hydroxy-pyridyl radical (see e.g. radical R₃ of thebelow-mentioned Examples 115-120). In such compounds the2-hydroxy-pyridyl radical can also be present as pyrid-2(1H)-on-yl.

Asymmetric carbon atoms of a compound of formula I that are optionallypresent may exist in the (R), (S) or (R,S) configuration, preferably inthe (R) or (S) configuration. Substituents at a double bond or a ringmay be present in cis- (═Z—) or trans (═E—) form. The compounds may thusbe present as mixtures of isomers or preferably as pure isomers.

Preferably alkyl contains up to 20 carbon atoms and is most preferablylower alkyl.

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either unbranched or branched withsingle or multiple branching.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl or n-heptyl.

Alkyl R₁ and R₂ independently of each other are preferably methyl,ethyl, isopropyl or tert-butyl, especially methyl or ethyl.

Lower alkyl Y is preferably methyl, ethyl or propyl.

Lower alkoxy is for example ethoxy or methoxy, especially methoxy.

Substituted alkyl is preferably lower alkyl as defined above where oneor more, preferably one, substituents may be present, such as e.g.amino, N-lower alkylamino, N,N-di-lower alkylamino, N-loweralkanoylamino, N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, loweralkanoyl, lower alkanoyloxy, cyano, nitro, carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio,halogen or a heterocyclic radical.

Substituted alkyl R₁ and R₂ are independently of each other preferablyhydroxy-lower alkyl, N,N-di-lower alkylamino-lower alkyl ormorpholinyl-lower alkyl.

Preferably unsubstituted or substituted cycloalkyl R₁ or R₂ containsfrom 3 up to 20 carbon atoms and is especially unsubstituted or alsosubstituted C₃-C₆ cycloalkyl wherein the substituents are selected frome.g. unsubstituted or substituted lower alkyl, amino, N-loweralkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, N,N-di-loweralkanoylamino, hydroxy, lower alkoxy, lower alkanoyl, lower alkanoyloxy,cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, amidino, guanidino,ureido, mercapto, lower alkylthio, halogen or a heterocyclic radical.

Mono- or disubstituted amino is amino substituted by one or two radicalsselected independently of one another from e.g. unsubstituted orsubstituted lower alkyl.

Disubstituted amino R₄ is preferably N,N-di-lower alkylamino, especiallyN,N-dimethylamino or N,N-diethylamino.

A heterocyclic radical contains especially up to 20 carbon atoms and ispreferably a saturated or unsaturated monocyclic radical having from 4or 8 ring members and from 1 to 3 heteroatoms which are preferablyselected from nitrogen, oxygen and sulfur, or a bi- or tri-cyclicradical wherein, for example, one or two carbocyclic radicals, such ase.g. benzene radicals, are annellated (fused) to the mentionedmonocyclic radical. If a heterocyclic radical contains a fusedcarbocyclic radical then the heterocyclic radical may also be attachedto the rest of the molecule of formula I via a ring atom of the fusedcarbocyclic radical. The heterocyclic radical (including the fusedcarbocyclic radical(s) if present) is optionally substituted by one ormore, preferably by one or two, radicals such as e.g. unsubstituted orsubstituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio,or halogen.

Most preferably a heterocyclic radical is pyrrolidinyl, piperidyl,piperazinyl, lower alkyl-piperazinyl, di-lower alkyl-piperazinyl,morpholinyl, tetrahydropyranyl, pyridyl, pyridyl substituted by hydroxyor lower alkoxy, or benzodioxolyl, especially pyrrolidinyl, piperidyl,lower alkyl-piperazinyl, di-lower alkyl-piperazinyl or morpholinyl.

A heterocyclic radical R₁ or R₂ is as defined above for a heterocyclicradical with the proviso that it is bonded to the rest of the moleculeof formula I via a ring carbon atom. Preferably a heterocyclic radicalR₁ or R₂ is lower alkyl-piperazinyl or especially preferredtetrahydropyranyl. If one of the two radicals R₁ and R₂ represents aheterocyclic radical, the other is preferably hydrogen.

A heterocyclic radical R₃ is as defined above for a heterocyclic radicalwith the proviso that it is bonded to Q via a ring carbon atom if X isnot present. Preferably a heterocyclic radical R₃ is benzodioxolyl,pyridyl substituted by hydroxy or lower alkoxy, or especially preferredindolyl substituted by halogen and lower alkyl. If R₃ is pyridylsubstituted by hydroxy then the hydroxy group is preferably attached toa ring carbon atom adjacent to the ring nitrogen atom.

A heterocyclic radical R₄ is as defined above for a heterocyclic radicaland is preferably pyrrolidinyl, piperidyl, lower alkyl-piperazinyl,morpholinyl or pyridyl.

If R₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical, the heterocyclic radical is as definedabove for a heterocyclic radical and represents preferably pyrrolidinyl,piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl or morpholinyl.

An unsubstituted or substituted aromatic radical R₃ has up to 20 carbonatoms and is unsubstituted or substituted, for example in each caseunsubstituted or substituted phenyl. Preferably an unsubstitutedaromatic radical R₃ is phenyl. A substituted aromatic radical R₃ ispreferably phenyl substituted by one or more substituents selectedindependently of one another from the group consisting of unsubstitutedor substituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthioand halogen. Most preferably a substituted aromatic radical R₃ is phenylsubstituted by one or more radicals selected independently of oneanother from the group consisting of lower alkyl, amino, hydroxy, loweralkoxy, halogen and benzyloxy.

Halogen is primarily fluoro, chloro, bromo or iodo, especially fluoro,chloro or bromo.

C₁-C₇-alkylene may be branched or unbranched and is in particularC₁-C₃-alkylene.

C₁-C₇-alkylene G is preferably C₁-C₃-alkylene, most preferably methylene(—CH₂—).

If G is not C₁-C₇-alkylene it preferably represents —C(═O)—.

C₁-C₇-alkylene X is preferably C₁-C₃-alkylene, most preferably methylene(—CH₂—) or ethan-1,1-diyl (—CH(CH₃)—).

Q is preferably —NH—.

Z is preferably oxygen or sulfur, most preferably oxygen.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula I with abasic nitrogen atom, especially the pharmaceutically acceptable salts.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, or ammoniumsalts with ammonia or suitable organic amines, such as tertiarymonoamines.

In the presence of a basic group and an acid group in the same molecule,a compound of formula I may also form internal salts.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. Only the pharmaceutically acceptable salts or freecompounds (if the occasion arises, in the form of pharmaceuticalcompositions) attain therapeutic use, and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including those salts that can beused as intermediates, for example in the purification or identificationof the novel compounds, hereinbefore and hereinafter any reference tothe free compounds is to be understood as referring also to thecorresponding salts, as appropriate and expedient.

The compounds of formula I have valuable, pharmacologically usefulproperties. In particular they exhibit specific inhibitory activitiesthat are of pharmacological interest. They are effective especially asprotein tyrosine kinase inhibitors and/or (furthermore) as inhibitors ofserine/threonine protein kinases; they exhibit, for example, powerfulinhibition of the tyrosine kinase activity of the epidermal growthfactor receptor (EGF-R) and of ErbB-2 kinase. These two protein tyrosinekinase receptors, together with their family members ErbB-3 and ErbB-4,play a key role in signal transmission in a large number of mammaliancells, including human cells, especially epithelial cells, cells of theimmune system and cells of the central and peripheral nervous system.For example, in various cell types, EGF-induced activation ofreceptor-associated protein tyrosine kinase is a prerequisite for celldivision and hence for the proliferation of the cell population. Mostimportantly, overexpression of the EGF-R (HER-1) and/or ErbB-2 (HER-2)has been observed in substantial fractions of many human tumours. EGF-R,e.g., was found to be overexpressed in non small-cell lung cancers,squamous carcinoma (head and neck), breast, gastric, ovarian, colon andprostate cancers as well as in gliomas. ErbB-2 was found to beoverexpressed in squamous carcinoma (head and neck), breast, gastric,and ovarian cancers as well as in gliomas.

In addition to inhibiting the tyrosine kinase activity of the EGF-R, thecompounds of formula I also inhibit to varying extents other proteintyrosine kinases that are involved in signal transmission mediated bytrophic factors, specially the vascular endothelial growth factor (VEGF)receptor family (e.g. KDR, Flt-1, Flt-3) but also abl kinase, especiallyv-abl, kinases from the family of Src, especially c-Src, Lck and Fyn,the other members of the EGF receptor family such as ErbB-3 (HER-3) andErbB-4 (HER-4), CSF-1, Kit, FGF receptor and the cyclin-dependentkinases CDK1 and CDK2, all of which play a part in growth regulation andtransformation in mammalian cells, including human cells.

The inhibition of EGF-R tyrosine kinase activity can be demonstratedusing known methods, for example using the recombinant intracellulardomain of the EGF-receptor [EGF-R ICD; see, for example, E. McGlynn etal., Europ. J. Biochem. 207, 265-275 (1992)]. Compared with the controlwithout inhibitor, the compounds of formula I inhibit the enzymeactivity by 50% (IC₅₀), for example in a concentration of from 0.0005 to0.5 μM, especially from 0.001 to 0.1 μM.

As well as or instead of inhibiting EGF-R tyrosine kinase activity, thecompounds of formula I also inhibit other members of this family ofreceptors, like ErbB-2. The inhibitory activity (IC₅₀) is approximatelyin the range of 0.001 to 0.5 μM. The inhibition of ErbB-2 tyrosinekinase (HER-2) can be determined, for example, analogously to the methodused for EGF-R protein tyrosine kinase [see C. House et al., Europ. J.Biochem. 140, 363-367 (1984)]. The ErbB-2 kinase can be isolated, andits activity determined, by means of protocols known per se, for examplein accordance with T. Akiyama et al., Science 232, 1644 (1986).

Surprisingly, the compounds of formula I especially also inhibit thetyrosine kinase activity of the VEGF receptor family very potently. Thecompounds of the present invention are therefore very effective dualinhibitors of EGF- and VEGF-receptor family members. For inhibition ofKDR and Flt-1 and inhibition of growth factor-induced proliferation ofHUVECS see J. Wood et al., Cancer Res. 60, 2178-2189 (2000). Thecompounds of formula I inhibit e.g. the KDR tyrosine kinase activitywith an IC₅₀ of from about 1 nM to about 1 μM, especially from about 5nM to about 0.5 μM.

The action of the compounds of formula I on EGF-induced phosphorylationof the EGF-R can be determined in the human A431 epithelial carcinomacell line by means of an ELISA which is described in U. Trinks et al.,J. Med. Chem. 37:7, 1015-1027 (1994). In that test (EGF-R ELISA) thecompounds of formula I exhibit an IC₅₀ of approximately from 0.001 to 1μM.

The compounds of formula I potently inhibit the growth of EGF-Roverexpressing NCl-H596 non-small cell lung carcinoma cells [see e.g. W.Lei, et al., Anticancer Res. 19(1A), 221-228 (1999)] at an IC₅₀ ofapproximately 0.01 to 1 μM. In the same range of activity, the compoundsof formula I also potently inhibit the growth of ErbB-2-overexpressingBT474 human breast cancer cells. The test procedures are adapted from T.Meyer et al., Int. J. Cancer 43, 851 (1989). The inhibitory activity ofthe compounds of formula I is determined, briefly, as follows: NCl-H596cells (10 000/microtitre plate well) are transferred to 96-wellmicrotitre plates. The test compounds [dissolved in dimethyl sulfoxide(DMSO)] are added in a series of concentrations (dilution series) insuch a manner that the final concentration of DMSO is not greater than1% (v/v). After the addition, the plates are incubated for three daysduring which the control cultures without test compound are able toundergo at least three cell-division cycles. The growth of the NCl-H596cells is measured by means of methylene blue staining: after theincubation the cells are fixed with glutaraldehyde, washed with waterand stained with 0.05% methylene blue. After a washing step the stain iseluted with 3% HCl and the optical density (OD) per well of themicrotitre plate is measured using a Titertek Multiskan (Titertek,Huntsville, Ala., USA) at 665 nm. IC₅₀ values are determined by acomputer-aided system using the formula:IC ₅₀=[(OD _(test) −OD _(start))/(OD _(control) −OD _(start))]×100.

The IC₅₀ value in those experiments is given as that concentration ofthe test compound in question that results in a cell count that is 50%lower than that obtained using the control without inhibitor. Thecompounds of formula I exhibit inhibitory activity with an IC₅₀ in therange from approximately 0.01 to 1 μM.

The compounds of formula I exhibit inhibition of the growth of tumourcells also in vivo, as shown, for example, by the test described below:the test is based on inhibition of the growth of the human squamous lungcarcinoma cell line NCl-H596 [ATCC HTB 178; American Type CultureCollection, Rockville, Md., USA; see Santon, J. B., et al., CancerResearch 46, 4701-4705 (1986) and Ozawa, S., et al., Int. J. Cancer 40,706-710 (1987)], which is transplanted into female BALB/c nude mice(Bomholtgard, Denmark). That carcinoma exhibits a growth that correlateswith the extent of the expression of the EGF-R. Tumours are establishedafter subcutaneous (s.c.) injection of cells [a minimum of 2×10⁶ cellsin 100 μl phosphate-buffered saline (PBS) or medium] in carrier mice(4-8 mice). Injections are made s.c. in the left flank of the mousemid-way between the tail and the head. The resulting tumours areserially passaged for a minimum of three consecutive transplantationsprior to start of the treatment. During this time tumour growth ratesstabilize. Tumours are not passaged more than 12 times. For the therapyexperiment tumour fragments of roughly 25 mg are transplanted s.c. intothe left flank of the animals using a 13-gauge trocar needle underForene® (Abbott, Schwitzerland) anesthesia. Tumour growth and bodyweights are monitored twice per week. All treatments are initiated whenthe tumour attains a volume of 100 to 250 mm³. The tumour volumes arecalculated using the known formula Length×Diameter²×π/6 [see Evans, B.D., et al., Brit. J. Cancer 45, 466-8 (1982)]. Antitumour activity isexpressed as T/C % (mean increase of tumour volumes of treated animalsdivided by the mean increase of tumour volumes of control animalsmultiplied by 100%). At a dose of from 3 to 100 mg/kg of activeingredient, distinct inhibition of the tumour growth is found, forexample T/C % values of less than 50.

The compounds of formula I may inhibit other protein tyrosine kinasesthat are involved in signal transmission mediated by trophic factors,for example abl kinase, such as especially v-abl kinase (IC₅₀ forexample from 0.01 to 5 μM), kinases from the family of the src kinases,such as especially c-src kinase (IC₅₀ for example from 0.1 to 10 μM) andserine/threonine kinases, for example protein kinase C, all of which areinvolved in growth regulation and transformation in mammalian cells,including human cells.

The above-mentioned inhibition of v-abl tyrosine kinase is determined bythe methods of N. Lydon et al., Oncogene Research 5, 161-173 (1990) andJ. F. Geissler et al., Cancer Research 52, 4492-4498 (1992). In thosemethods [Val⁵]-angiotensin II and [γ³² P]-ATP are used as substrates.

The compounds of formula I which inhibit the tyrosine kinase activity ofthe EGF-R or of the other protein tyrosine kinases mentioned aretherefore useful, for example, in the treatment of benign or malignanttumours. The compounds of formula I are e.g. able to simultaneouslyinhibit the growth of tumors with deregulated EGF-R and/or ErbB-2activity as well as to inhibit the vascularisation of solid tumorstriggered by VEGF. This combined activity leads to an improvedantitumour effect (see also WO 02/41882). Moreover, the use of a dualinhibitor reduces the risk of drug-drug interactions and further reducesthe total drug load as compared to a combination therapy. The compoundsof formula I are capable of slowing down tumor growth or effectingtumour regression and of preventing the formation of tumour metastasesand the growth of micrometastases. They can be used especially in thecase of epidermal hyperproliferation (psoriasis), in the treatment ofneoplasias of epithelial character, e.g. mammary carcinomas, and inleukaemias. In addition, the compounds of formula I can be used in thetreatment of those disorders of the immune system in which several or,especially, individual protein tyrosine kinases and/or (furthermore)serine/threonine protein kinases are involved; the compounds of formulaI can also be used in the treatment of those disorders of the central orperipheral nervous system in which signal transmission by several or,especially, a single protein tyrosine kinase(s) and/or (furthermore)serine/threonine protein kinase(s) is/are involved.

In general, the present invention relates also to the use of thecompounds of formula I for the inhibition of the mentioned proteinkinases, in particular to their use for the dual inhibition of EGF- andVEGF-receptor family members.

The compounds according to the invention can be used both alone and incombination with other pharmacologically active compounds, for exampletogether with inhibitors of the enzymes of polyamine synthesis,inhibitors of protein kinase C, inhibitors of other tyrosine kinases,cytokines, negative growth regulators, for example TGF-β or IFN-β,aromatase inhibitors, antioestrogens and/or cytostatic drugs.

With the groups of preferred compounds of formula I mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred.

Preference is given to a compound of formula I, wherein

R₁ and R₂ are each independently of the other hydrogen, unsubstituted orsubstituted alkyl or cycloalkyl, a heterocyclic radical bonded via aring carbon atom, or a radical of the formula R₄—Y—(C═Z)— wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radical, Yis either not present or lower alkyl and Z is oxygen or sulfur or imino,with the proviso that R₁ and R₂ are not both hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical;R₃ is a heterocyclic radical or an unsubstituted or substituted aromaticradical;G is C₁-C₇-alkylene;Q is —NH— or —O—; andX is either not present or C₁-C₇-alkylene, with the proviso that aheterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;or a salt thereof.

Preference is further given to a compound of formula I, wherein

R₁ and R₂ are each independently of the other hydrogen, unsubstituted orsubstituted alkyl or cycloalkyl, a heterocyclic radical bonded via aring carbon atom, or a radical of the formula R₄—Y—(C═Z)— wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radical, Yis either not present or lower alkyl and Z is oxygen, sulfur or imino,with the proviso that R₁ and R₂ are not both hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical;R₃ is a heterocyclic radical or an unsubstituted or substituted aromaticradical;G is C₁-C₇alkylene;Q is —NH—; andX is either not present or C₁-C₇-alkylene, with the proviso that aheterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;or a salt thereof.

Special preference is given to a compound of formula I, wherein

R₁ and R₂ are each independently of the other hydrogen, unsubstituted orsubstituted lower alkyl or C₃-C₆ cycloalkyl, a heterocyclic radicalbonded via a ring carbon atom and containing up to 20 carbon atoms, or aradical of the formula R₄—Y—(C═Z)— wherein R₄ is unsubstituted, mono- ordisubstituted amino or a heterocyclic radical containing up to 20 carbonatoms, Y is either not present or lower alkyl and Z is oxygen, with theproviso that R₁ and R₂ are not both hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical containing up to 20 carbon atoms;R₃ is a heterocyclic radical containing up to 20 carbon atoms or anunsubstituted or substituted aromatic radical having up to 20 carbonatoms;G is C₁-C₃-alkylene;Q is —NH—; andX is either not present or C₁-C₃-alkylene, with the proviso that aheterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent;or a salt thereof.

Special preference is further given to a compound of formula I, wherein

R₁ and R₂ are each independently of the other hydrogen, lower alkyl,hydroxy-lower alkyl, N,N-di-lower alkylamino-lower alkyl,morpholinyl-lower alkyl, tetrahydropyranyl, or a radical of the formulaR₄—Y—(C═Z)— wherein R₄ is di-lower alkylamino, pyrrolidinyl, piperidyl,lower alkyl-piperazinyl, morpholinyl or pyridyl, Y is either not presentor lower alkyl and Z is oxygen, with the proviso that R₁ and R₂ are notboth hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are attachedform a radical selected from the group consisting of pyrrolidinyl,piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl and morpholinyl;R₃ is phenyl, benzodioxolyl, pyridyl substituted by hydroxy or loweralkoxy, indolyl substituted by halogen and lower alkyl, or phenylsubstituted by one or more radicals selected independently of oneanother from the group consisting of lower alkyl, hydroxy, lower alkoxy,halogen and benzyloxy;G is —CH₂— or —C(═O)—;Q is —NH— or —O—, with the proviso that Q is —O— if G is —C(═O)—; andX is either not present, —CH₂— or —CH(CH₃)—, with the proviso thatsubstituted pyridyl or indolyl R₃ is bonded via a ring carbon atom if Xis not present;or a salt thereof.

Special preference is further also given to a compound of formula I,wherein

R₁ and R₂ are each independently of the other hydrogen, lower alkyl,hydroxy-lower alkyl, or a radical of the formula R₄—Y—(C═Z)— wherein R₄is di-lower alkylamino, pyrrolidinyl, piperidyl, loweralkyl-piperazinyl, morpholinyl or pyridyl, Y is either not present orlower alkyl and Z is oxygen, with the proviso that R₁ and R₂ are notboth hydrogen; orR₁ and R₂ together with the nitrogen atom to which they are attachedform a radical selected from the group consisting of pyrrolidinyl,piperidyl, piperazinyl, lower alkyl-piperazinyl, di-loweralkyl-piperazinyl and morpholinyl;R₃ is phenyl, benzodioxolyl, pyridyl substituted by hydroxy or loweralkoxy, or phenyl substituted by one or more radicals selectedindependently of one another from the group consisting of lower alkyl,hydroxy, lower alkoxy, halogen and benzyloxy;G is —CH₂—;Q is —NH—; andX is either not present, —CH₂— or —CH(CH₃)—, with the proviso thatsubstituted pyridyl R₃ is bonded via a ring carbon atom if X is notpresent;or a salt thereof.

Special preference is also given to a compound of formula I whereinC₁-C₇-alkylene G is attached to the phenyl ring at position 3 or 4, mostespecially at position 4.

Very special preference is further given to a compound of formula Imentioned in the Examples below, or a salt, especially apharmaceutically acceptable salt, thereof.

Also especially preferred are compounds of formula I, which—according tothe above-described tyrosine kinase inhibition assays—inhibit HER-1,HER-2 and KDR with IC₅₀ values of less than 300 nM, most preferably ofless than 100 nM.

Very special preference is further given to compounds of formula I whichinhibit the tyrosine kinase activity of at least one member of the EGFreceptor family together with at least one member of the VEGF receptorfamily (dual inhibition of EGF- and VEGF-receptor family members) withIC₅₀ values in the range of 0.5 nM to 0.5 μM, especially in the range of1 nM to 300 nM, based on the above-described tyrosine kinase inhibitionassays.

Especially preferred are further also compounds of formula I in which Gis C₁-C₇-alkylene since the amine group of such compounds allows togenerate pharmaceutically acceptable salts of these compounds which ingeneral leads to an increased solubility and to improvedphysico-chemical properties.

The compounds of formula I or salts thereof are prepared in accordancewith processes known per se (see also EP 682 027, WO 97/02266, WO97/27199 and WO 98/07726), though not previously described for themanufacture of the compounds of the formula I, especially whereby

a) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene and wherein R₁ and R₂ are each independently of the otherhydrogen, unsubstituted or substituted alkyl or cycloalkyl, or aheterocyclic radical bonded via a ring carbon atom, with the provisothat R₁ and R₂ are not both hydrogen, or wherein R₁ and R₂ together withthe nitrogen atom to which they are attached form a heterocyclicradical, a compound of the formula II

wherein Hal is halogen, G is C₁-C₇-alkylene and R₃, Q and X have themeanings as defined for a compound of formula I, is reacted with acompound of the formula III

wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, or a heterocyclicradical bonded via a ring carbon atom, with the proviso that R₁ and R₂are not both hydrogen, or wherein R₁ and R₂ together with the nitrogenatom to which they are attached form a heterocyclic radical;b) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene and wherein R₁ is a radical of the formula R₄—Y—(C═Z)—wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen or sulfur,(i) a compound of the formula IV

wherein Hal is halogen, G is C₁-C₇-alkylene, Z is oxygen and theremaining substituents and symbols have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof the formula R₄—H wherein R₄ is unsubstituted, mono- or disubstitutedamino or a heterocyclic radical containing at least one nitrogen ringatom wherein the heterocyclic radical is attached to the hydrogen atomof R₄—H via a nitrogen ring atom, or(ii) a compound of the formula V

wherein G is C₁-C₇-alkylene and the remaining substituents and symbolshave the meanings as defined for a compound of formula I, is reactedwith a compound of the formula VI

wherein R₄ and Y have the meanings as defined above under formula I andZ is oxygen,whereby a compound of formula I which results from process b) (i) or(ii) is optionally converted into the respective compound wherein Z issulfur;c) in order to prepare a compound of formula I, wherein G is —C(═O)— orC₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attached to theNR₁R₂ moiety, a compound of formula XI

wherein the substituents and symbols have the meanings as defined for acompound of formula I, is reacted with a compound of formula XII

wherein R₁ and R₂ have the meanings as defined for a compound of formulaI; ord) in order to prepare a compound of formula I, wherein G isC₁-C₇-alkylene, a compound of formula I, wherein G is —C(═O)— orC₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attached to theNR₁R₂ moiety, is reacted with a reducing agent to produce thecorresponding compound in which G is C₁-C₇-alkylene;whereby functional groups which are present in the starting compounds ofprocesses a) to d) and are not intended to take part in the reaction,are present in protected form if necessary, and protecting groups thatare present are cleaved, whereby the said starting compounds may alsoexist in the form of salts provided that a salt-forming group is presentand a reaction in salt form is possible;and, if so desired, a compound of formula I thus obtained is convertedinto another compound of formula I, a free compound of formula I isconverted into a salt, an obtained salt of a compound of formula I isconverted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.Description of the Process Variants:Regarding Process a):

The reaction between a compound of formula II and a compound of formulaIII preferably takes place in a suitable inert solvent, especiallyN,N-dimethylformamide, in the presence of a base such as potassiumcarbonate, at temperatures from room temperature (RT) to 100° C.Alternatively, the reaction between a compound of formula II and acompound of formula III takes place in a suitable solvent, e.g. loweralcohols, such as ethanol, in the presence of for example a suitablecatalyst such as NaI, preferably at the reflux temperature of thesolvent employed. In a compound of formula II, Hal is preferably chloro.

Regarding Process b):

(i) The reaction of a compound of formula IV and a compound of theformula R₄—H preferably takes place in a suitable solvent, especiallyalcohols, e.g. lower alcohols such as n-butanol, at elevatedtemperature, preferably near the boiling temperature of the solventemployed. In a compound of formula IV, Hal is preferably chloro.

(ii) The reaction between a compound of formula V and a compound offormula VI preferably takes place in the presence ofO-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate(TPTU) and N,N-diisopropylethylamine, or in the presence of(benzotriazole-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoroborate(BOP) and N-methylmorpholin, in a suitable inert solvent, such as forexample N,N-dimethylformamide, preferably at RT.

A compound of formula I which results from process b) (i) or (ii) can beconverted into the respective compound of formula I wherein Z is sulfur,for example, by using an appropriate sulfur compound, e.g. usingreaction with Lawesson's reagent(2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithia-phosphetan) in ahalogenated carbon hydrate, such as dichloromethane, or an aproticsolvent, such as toluene or xylene, at temperatures from about 30° C. toreflux.

Regarding Process c):

The reaction of a compound of formula XI with a compound of formula XIIpreferably takes place in a suitable inert solvent such asN,N-dimethylformamide and in an inert, for example an argon or nitrogen,atmosphere, in the presence of diethyl-cyanphosphonate, preferably atabout 0° C.

Regarding Process d):

The reducing agent used in process d) is preferably lithium aluminiumhydride or diisobutyl-aluminium hydride. The reaction preferably takesplace under those conditions described in Example 79 or 141,respectively.

Additional Process Steps

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more protecting groups. The protecting groups are thenwholly or partly removed according to one of the known methods.

Protecting groups, and the manner in which they are introduced andremoved are described, for example, in “Protective Groups in OrganicChemistry”, Plenum Press, London, New York 1973, and in “Methoden derorganischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene,“Protective Groups in Organic Synthesis”, John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be removedreadily, i.e. without the occurrence of undesired secondary reactions,for example by solvolysis, reduction, photolysis or alternatively underphysiological conditions.

The end products of formula I may however also contain substituents thatcan also be used as protecting groups in starting materials for thepreparation of other end products of formula I. Thus, within the scopeof this text, only a readily removable group that is not a constituentof the particular desired end product of formula I is designated a“protecting group”, unless the context indicates otherwise.

General Process Conditions

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably those that are inert to the reagents used and able todissolve them, in the absence or presence of catalysts, condensingagents or neutralising agents, for example ion exchangers, typicallycation exchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at RT, at−20 to 40° C., at 0 to 100° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, if need be underpressure, and/or in an inert, for example an argon or nitrogen,atmosphere.

The invention relates also to those embodiments of the process in whichone starts from a compound obtainable at any stage as an intermediateand carries out the missing steps, or breaks off the process at anystage, or forms a starting material under the reaction conditions, oruses said starting material in the form of a reactive derivative orsalt, or produces a compound obtainable by means of the processaccording to the invention under those process conditions, and furtherprocesses the said compound in situ. In the preferred embodiment, onestarts from those starting materials which lead to the compoundsdescribed hereinabove as preferred.

In the preferred embodiment, a compound of formula I is preparedaccording to the processes and process steps defined in the Examples.

The compounds of formula I, including their salts, are also obtainablein the form of hydrates, or their crystals can include for example thesolvent used for crystallisation (present as solvates).

Starting Materials

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inthe preferred embodiment, such starting materials are used and reactionconditions so selected as to enable the preferred compounds to beobtained.

The starting materials used in the above described processes a) to b)are known, capable of being prepared according to known processes (seealso EP 682 027, WO 97/02266, WO 97/27199 and WO 98/07726), orcommercially obtainable; in particular, they can be prepared usingprocesses as described in the Examples.

In the preparation of starting materials, existing functional groupswhich do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the Examples. In place of therespective starting materials and transients, salts thereof may also beused for the reaction, provided that salt-forming groups are present andthe reaction with a salt is also possible. Where the term startingmaterials is used hereinbefore and hereinafter, the salts thereof arealways included, insofar as reasonable and possible.

A compound of formula II can be prepared for example by reacting acompound of formula VII

wherein G is C₁-C₇-alkylene and R₃, Q and X have the meanings as definedfor a compound of formula I, with e.g. thionyl halogenide, preferablythionyl chloride, in the presence or absence of pyridine, in an inertsolvent, for example toluene or in a 1:1 mixture of acetonitrile anddioxane, preferably at −10 to 0° C. or at RT.

A compound of formula VII can be prepared for example by reacting acompound of formula VIII

wherein R₅ is lower alkyl, especially methyl or ethyl, and R₃, Q and Xhave the meanings as defined for a compound of formula I, with lithiumaluminium hydride, in an inert solvent, especially ethers, e.g. cyclicethers such as tetrahydrofuran, preferably at the reflux temperature ofthe solvent employed. Alternatively, a compound of formula VII may beprepared by reacting a compound of formula VIII withdiisobutyl-aluminium hydride, in an inert solvent, for example intetrahydrofuran or in a 1:1 mixture of dichloromethane and dioxane,preferably at RT.

A compound of formula VIII wherein Q is —NH— can be prepared for exampleby reacting a compound of formula IX

wherein Hal is halogen, preferably chloro, and R₅ is as defined abovefor a compound of formula VIII, with a compound of the formula H₂N—X—R₃,wherein R₃ and X have the meanings as defined for a compound of formulaI, (i) in a suitable solvent such as alcohols, especially lower alcoholssuch as n-butanol, preferably at the boiling temperature of the solventemployed or (ii) under catalytic conditions e.g. according to theBuchwald reaction conditions such as those described in Step 133.1 ofExample 133 below.

A compound of formula VIII wherein Q is —O— can be prepared for exampleby reacting a compound of formula IX, which is preferably N-protected inthe pyrrolo-pyrimidine moiety, with a compound of the formula HO—X—R₃,wherein R₃ and X have the meanings as defined for a compound of formulaI, in a suitable inert solvent such as N,N-dimethylformamide and in thepresence of a base such as potassium carbonate, at elevatedtemperatures, preferably at around 100° C.

Alternatively, the carboxylic acid ester of a compound of formula IX mayfirst be reduced to the corresponding alcohol, e.g. under conditionsdescribed above for the preparation of a compound of formula VII, andthen either be reacted with a compound of the formula H₂N—X—R₃, e.g.under conditions described above for the preparation of a compound offormula VIII wherein Q is —NH—, or be reacted with a compound of theformula HO—X—R₃, e.g. under conditions described above for thepreparation of a compound of formula VIII wherein Q is —O—.

A compound of formula IV can be prepared for example by reacting acompound of formula V with a compound of the formula X

wherein Hal is Halogen, preferably chloro, Y has the meanings as definedabove under formula I, and Z is oxygen, in the presence oftriethylamine, in an inert solvent such as e.g. tetrahydrofuran,preferably at RT.

A compound of formula X1 can be prepared for example by reacting acompound of formula VIII with LiOH, preferably in a mixture of dioxaneand water, at elevated temperatures, preferably under those conditionsdescribed in Step 141.4 of Example 141 below.

The remaining starting materials are known, capable of being preparedaccording to known processes, or commercially available; or inparticular, they can be prepared using processes as described in theExamples.

Pharmaceutical Compositions, Methods, and Uses

The present invention relates also to pharmaceutical compositions thatcomprise a compound of formula I, or a pharmaceutically acceptable saltthereof, as active ingredient and that can be used especially in thetreatment of the diseases mentioned at the beginning. Compositions forenteral administration, such as nasal, buccal, rectal or, especially,oral administration, and for parenteral administration, such asintravenous, intramuscular or subcutaneous administration, towarm-blooded animals, especially humans, are especially preferred. Thecompositions contain the active ingredient alone or, preferably,together with a pharmaceutically acceptable carrier. The dosage of theactive ingredient depends upon the disease to be treated and upon thespecies, its age, weight, and individual condition, the individualpharmacokinetic data, and the mode of administration.

The present invention also relates to pro-drugs of a compound of formulaI that convert in vivo to the compound of formula I as such. Anyreference to a compound of formula I is therefore to be understood asreferring also to the corresponding pro-drugs of the compound of formulaI, as appropriate and expedient.

The invention relates also to compounds of formula I, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition, for use in a method for the prophylactic orespecially therapeutic treatment of the human or animal body, to aprocess for the preparation thereof (especially in the form ofcompositions for the treatment of tumours) and to a method of treatingproliferative diseases, primarily tumour diseases, especially thosementioned above.

The invention relates also to processes and to the use of compounds offormula I, or a pharmaceutically acceptable salt thereof, for thepreparation of pharmaceutical compositions which comprise compounds offormula I, or a pharmaceutically acceptable salt thereof, as activecomponent (active ingredient).

If desired, the said pharmaceutical compositions may also containfurther active components, for example cytostatics, and/or may be usedin combination with known therapeutic processes, for example theadministration of hormones or radiation.

Preference is given for a pharmaceutical composition which is suitablefor administration to a warm-blooded animal, especially humans orcommercially useful mammals suffering from a disease which responds toan inhibition of a protein tyrosine kinase, especially to a dualinhibition of EGF- and VEGF-receptor family members, especially aneoplastic disease, comprising an effective quantity of a compound offormula I for the inhibition of a protein tyrosine kinase, especiallyfor the dual inhibition of EGF- and VEGF-receptor family members, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier.

A pharmaceutical composition for the prophylactic or especiallytherapeutic management of neoplastic and other proliferative diseases ofa warm-blooded animal, especially a human or a commercially usefulmammal requiring such treatment, especially suffering from such adisease, comprising as active ingredient in a quantity that isprophylactically or especially therapeutically active against saiddiseases a compound of formula I, or a pharmaceutically acceptable saltthereof, is likewise preferred.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories or capsules. Examples are capsules containing from about0.05 g to about 1.0 g of active substance.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilising processes.

The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of a proteintyrosine kinase, especially to a dual inhibition of EGF- andVEGF-receptor family members, especially a corresponding neoplasticdisease. The compounds of formula I, or pharmaceutically acceptablesalts thereof, can be administered as such or in the form ofpharmaceutical compositions, prophylactically or therapeutically,preferably in an amount effective against the said diseases, to awarm-blooded animal, for example a human, requiring such treatment, thecompounds especially being used in the form of pharmaceuticalcompositions. In the case of an individual having a bodyweight of about70 kg the daily dose administered is from approximately 0.1 g toapproximately 5 g, preferably from approximately 0.5 g to approximately2 g, of a compound of the present invention.

The present invention relates especially also to the use of a compoundof formula I, or a pharmaceutically acceptable salt thereof, especiallya compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition with at least one pharmaceutically acceptablecarrier, for the therapeutic and also prophylactic management of one ormore of the diseases mentioned hereinabove, preferably a disease whichresponds to an inhibition of a protein tyrosine kinase, especially to adual inhibition of EGF- and VEGF-receptor family members, especially aneoplastic disease, in particular if the said disease responds to aninhibition of a protein tyrosine kinase, especially to a dual inhibitionof EGF- and VEGF-receptor family members.

The present invention relates especially also to the use of a compoundof formula I, or a pharmaceutically acceptable salt thereof, especiallya compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the therapeutic and also prophylacticmanagement of one or more of the diseases mentioned hereinabove,especially a neoplastic disease, in particular if the disease respondsto an inhibition of a protein tyrosine kinase, especially to a dualinhibition of EGF- and VEGF-receptor family members.

A compound of formula I may also be used to advantage in combinationwith other antiproliferative agents. Such antiproliferative agentsinclude, but are not limited to aromatase inhibitors, antiestrogens,topoisomerase I inhibitors, topoisomerase II inhibitors, microtubuleactive agents, alkylating agents, histone deacetylase inhibitors,farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTORinhibitors, antineoplastic antimetabolites, platin compounds, compoundsdecreasing the protein kinase activity and further anti-angiogeniccompounds, gonadorelin agonists, anti-androgens, bengamides,bisphosphonates, antiproliferative antibodies and temozolomide(TEMODAL®).

The term “aromatase inhibitors” as used herein relates to compoundswhich inhibit the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially exemestane and formestane and, in particular, non-steroids,especially aminoglutethimide, vorozole, fadrozole, anastrozole and, veryespecially, letrozole. Exemestane can be administered, e.g., in the formas it is marketed, e.g. under the trademark AROMASIN™. Formestane can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark LENTARON™. Fadrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark AFEMA™. Anastrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ARIMIDEX™. Letrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark FEMARA™ or FEMAR™.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN™.

A combination of the invention comprising an antineoplastic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive breast tumors.

The term “antiestrogens” as used herein relates to compounds whichantagonize the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX™.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA™. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FASLODEX™.

The term “topoisomerase I inhibitors” as used herein includes, but isnot limited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound A1 inWO99/17804). Irinotecan can be administered, e.g., in the form as it ismarketed, e.g. under the trademark CAMPTOSAR™. Topotecan can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HYCAMTIN™.

The term “topoisomerase II inhibitors” as used herein includes, but isnot limited to the antracyclines doxorubicin (including liposomalformulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinesetoposide and teniposide. Etoposide can be administered, e.g., in theform as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark VM 26-BRISTOL™. Doxorubicin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ADRIBLASTIN™.Epirubicin can be administered, e.g., in the form as it is marketed,e.g. under the trademark FARMORUBICIN™. Idarubicin can be administered,e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g. under the trademark NOVANTRON™.

The term “microtubule active agents” relates to microtubule stabilizingand microtubule destabilizing agents including, but not limited to thetaxanes paclitaxel and docetaxel, the vinca alkaloids, e.g.,vinblastine, especially vinblastine sulfate, vincristine especiallyvincristine sulfate, and vinorelbine, discodermolide and epothilones,such as epothilone B and D. Docetaxel can be administered, e.g., in theform as it is marketed, e.g. under the trademark TAXOTERE™. Vinblastinesulfate can be administered, e.g., in the form as it is marketed, e.g.under the trademark VINBLASTIN R.P.™. Vincristine sulfate can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FARMISTIN™. Discodermolide can be obtained, e.g., as disclosedin U.S. Pat. No. 5,010,099.

The term “alkylating agents” as used herein includes, but is not limitedto cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CYCLOSTIN™. Ifosfamide can be administered, e.g., in the formas it is marketed, e.g. under the trademark HOLOXAN™.

The term “histone deacetylase inhibitors” relates to compounds whichinhibit the histone deacetylase and which possess antiproliferativeactivity.

The term “farnesyl transferase inhibitors” relates to compounds whichinhibit the farnesyl transferase and which possess antiproliferativeactivity.

The term “COX-2 inhibitors” relates to compounds which inhibit thecyclooxygenase type 2 enzyme (COX-2) and which possess antiproliferativeactivity such as celecoxib (Celebrex®), rofecoxib (Vioxx®) andlumiracoxib (COX189).

The term “MMP inhibitors” relates to compounds which inhibit the matrixmetalloproteinase (MMP) and which possess antiproliferative activity.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCl-779and ABT578.

The term “antineoplastic antimetabolites” includes, but is not limitedto 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine,fludarabine phosphate, fluorouridine, gemcitabine, 6-mercaptopurine,hydroxyurea, methotrexate, edatrexate and salts of such compounds, andfurthermore ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618(LOMOTREXOL™) and OGT719.

The term “platin compounds” as used herein includes, but is not limitedto carboplatin, cisplatin and oxaliplatin. Carboplatin can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN™.

The term “compounds decreasing the protein kinase activity and furtheranti-angiogenic compounds” as used herein includes, but is not limitedto compounds which decrease the activity of e.g. the VascularEndothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF),c-Src, protein kinase C, Platelet-derived Growth Factor (PDGF), Bcr-Abltyrosine kinase, c-kit, Flt-3 and Insulin-like Growth Factor I Receptor(IGF-IR) and Cyclin-dependent kinases (CDKs), and anti-angiogeniccompounds having another mechanism of action than decreasing the proteinkinase activity.

Compounds which decrease the activity of VEGF are especially compoundswhich inhibit the VEGF receptor, especially the tyrosine kinase activityof the VEGF receptor, and compounds binding to VEGF, and are inparticular those compounds, proteins and monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958 (describingcompounds of formula I), WO 00/09495, WO 00/27820, WO 00/59509, WO98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0 769 947; thoseas described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218,by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27,no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin™,described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; andEndostatin™, described by M. S. O'Reilly et al, Cell 88, 1997, 277-285;

compounds which decrease the activity of EGF are especially compoundswhich inhibit the EGF receptor, especially the tyrosine kinase activityof the EGF receptor, and compounds binding to EGF, and are in particularthose compounds generically and specifically disclosed in WO 97/02266(describing compounds of formula IV), EP 0 564 409, WO 99/03854, EP0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, WO 98/10767, WO97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980;compounds which decrease the activity of c-Src include, but are notlimited to, compounds inhibiting the c-Src protein tyrosine kinaseactivity as defined below and to SH2 interaction inhibitors such asthose disclosed in WO97/07131: and WO97/08193;compounds inhibiting the c-Src protein tyrosine kinase activity include,but are not limited to, compounds belonging to the structure classes ofpyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines andpyridopyrimidines, especially pyrido[2,3-d]pyrimidines. Preferably, theterm relates to those compounds disclosed in WO 96/10028, WO 97/28161,WO97/32879 and WO97/49706;compounds which decreases the activity of the protein kinase C areespecially those staurosporine derivatives disclosed in EP 0 296 110(pharmaceutical preparation described in WO 00/48571) which compoundsare protein kinase C inhibitors;further specific compounds that decrease protein kinase activity andwhich may also be used in combination with the compounds of the presentinvention are Imatinib (Gleevec®/Glivec®), PKC412, Iressa™ (ZD1839),PKI166, PTK787, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214,CP-547632 and KRN-633; anti-angiogenic compounds having anothermechanism of action than decreasing the protein kinase activity include,but are not limited to e.g. thalidomide (THALOMID), celecoxib(Celebrex), SU5416 and ZD6126.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelixcan be formulated, eg. as disclosed in U.S. Pat. No. 5,843,901.

The term “anti-androgens” as used herein includes, but is not limited tobicalutamide (CASODEX™), which can be formulated, e.g. as disclosed inU.S. Pat. No. 4,636,505.

The term “bengamides” relates to bengamides and derivatives thereofhaving aniproliferative properties.

The term “bisphosphonates” as used herein includes, but is not limitedto etridonic acid, clodronic acid, tiludronic acid, pamidronic acid,alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.“Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, eg., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandrbnic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to trastuzumab (Herceptin™), Trastuzumab-DM1, erlotinib(Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553(anti-CD40) and 2C4 Antibody.

For the treatment of AML, compounds of formula I can be used incombination with standard leukemia therapies, especially in combinationwith therapies used for the treatment of AML. In particular, compoundsof formula I can be administered in combination with e.g.farnesyltransferase inhibitors and/or other drugs used for the treatmentof AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide,Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of formula I, can be prepared and administered as described inthe art such as in the documents cited above.

EXAMPLES

The following Examples serve to illustrate the invention withoutlimiting its scope.

Temperatures are measured in degrees Celsius. Unless otherwiseindicated, the reactions take place at RT.

The R_(f) values which indicate the ratio of the distance moved by eachsubstance to the distance moved by the eluent front are determined onsilica gel thin-layer plates (Merck, Darmstadt, Germany) by thin-layerchromatography using the respective named solvent systems.

If not otherwise indicated, the analytical HPLC conditions are asfollows:

-   Column: (250×4.6 mm) packed with reversed-phase material    C18-Nucleosil (5 μm mean particle size, with silica gel covalently    derivatized with octadecylsilanes, Macherey & Nagel, Düren,    Germany). Detection by UV absorption at 215 nm. The retention times    (t_(R)) are given in minutes. Flow rate: 1 ml/min.-   Gradient: 20%→100% a) in b) for 14 min+5 min 100% a). a):    Acetonitrile+0.05% TFA; b): water+0.05% TFA.

The short forms and abbreviations used have the following definitions:

BOC tert-butoxy-carbonyl conc. concentrated DMF N,N-dimethylformamideElem. anal. elemental analysis Et ethyl EtOAc ethyl acetate MS-ES massspectroscopy (electron spray) h hour(s) Me methyl MeOH methanol minminute(s) m.p. melting point RT room temperature TFA trifluoroaceticacid THF tetrahydrofuran (distilled over Na/benzophenone) TLC thin-layerchromatography t_(R) retention times

Example 1(3-Chloro-4-fluoro-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

A mixture of 200 mg (0.5 mmol) crude(3-chloro-4-fluoro-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminein 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33%solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) andthen heated under reflux for 1 h. The almost clear solution is cooledand the solvent evaporated. The residue is dissolved in a mixture ofdichloromethane and ethanol (95:5), washed with water, dried over sodiumsulfate and the solvent evaporated. Purification of the crude materialthrough flash chromatography using first dichloromethane/ethanol 95:5plus 1% conc. ammonia and then dichloromethane/ethanol 9:1 plus 1% conc.ammonia gives the title compound; m.p. 274-276° C.; MS-ES⁺: (M+H)⁺=396.

Step 1.14-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

3.6 g (12 mmol) 4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoicacid ethyl ester (WO 97/02266) are suspended in 80 ml n-butanol andtreated with 3.5 g (24 mmol) 3-chloro-4-fluoro-aniline. The mixture isheated to 145° C. under stirring. After 30 min a clear brown solution isobtained which turns into a thick suspension after 2 h. After a total of3 h the reaction mixture is cooled in an ice bath and the productcollected by filtration; m.p.>300° C.; R_(f)(dichloromethane/ethanol95:5 plus 1% conc. ammonia)=0.29; HPLC t_(R)=11.66 min.

Step 1.2{4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

570 mg (15 mmol) lithium aluminium hydride are suspended in 150 ml dryTHF at RT.4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester (1.23 g, 3 mmol) are added and the resulting mixture isheated to reflux for 1 h. The mixture is cooled in an ice bath andtreated sequentially with water (0.57 ml), 15% sodium hydroxide solution(0.57 ml) and water (1.71 ml). The solid aluminum complex is removed byfiltration (Hyflo Super Cel®; Fluka, Buchs, Switzerland), the filtratedried over sodium sulfate and the solvent evaporated. The residue wassuspended in water, filtered and dried to give the title compound;m.p.>300° C.; HPLC t_(R)=9.14 min.

Step 1.3(3-Chloro-4-fluoro-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

184 mg (0.5 mmol){4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolare suspended in 15 ml toluene. Pyridine (44 μl, 0.55 mmol) and thionylchloride (40 μl, 0.55 mmol) are added and the mixture is stirred at RTfor 16 h. A second portion of the same amounts of pyridine and thionylchloride are then added and the mixture stirred for 1 additional hour.The solvent is evaporated and the residue suspended in water containinga small amount of sodium bicarbonate (pH ˜8). After filtration, theproduct was thoroughly washed with water and ether and dried to givecrude title compound; m.p.>300° C.; R_(f)(dichloromethane/ethanol 95:5plus 1% conc. ammonia)=0.42; HPLC t_(R)=11.33 min.

Examples 2-8d

The following Examples are synthesized from(3-chloro-4-fluoro-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineusing an analogous procedure described in Example 1:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 2 (3-Chloro-4-fluoro- 285-287 424 0.32^(a) 8.54phenyl)-[6-(4-diethyl- aminomethyl-phenyl)- 7H-pyrrolo[2,3-d]-pyrimidin-4-yl]-amine 3 (3-Chloro-4-fluoro- 266-268 465 0.42^(b) 7.7phenyl)-{6-[4-(4- ethyl-piperazin-1- ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 4 (3-Chloro-4-fluoro- 268-270 422 0.45^(b) 8.4phenyl)-[6-(4-pyrrolidin- 1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]-pyrimidin-4-yl]-amine 5 (3-Chloro-4-fluoro- 264-266 451 0.33^(b) 7.5phenyl)-{6-[4-(4-methyl- piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 6 (3-Chloro-4-fluoro- 267-269 436 0.40^(b) 8.66phenyl)-[6-(4-piperidin- 1-ylmethyl-phenyl)-7H- pyrrolo[2,3-d]-pyrimidin-4-yl]-amine 7 (3-Chloro-4-fluoro- 298-300 438 0.21^(a) 8.07phenyl)-[6-(4-morpholin- 4-ylmethyl-phenyl)- 7H-pyrrolo[2,3-d]-pyrimidin-4-yl]-amine 8 (3-Chloro-4-fluoro- 261-263 465 0.35^(b) 7.53phenyl)-{6-[4-(3,5- dimethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl}-amine 8a (3-Chloro-4-fluoro- 288-290 4520.43^(c) 7.68 phenyl)-(6-{4-[(tetra- hydro-pyran-4-ylamino)-methyl]-phenyl}-7H- pyrrolo[2,3-d]- pyrimidin-4-yl)-amine 8b(3-Chloro-4-fluoro- 224-226 481 0.3^(d) 7.22 phenyl)-(6-{4-[(2-morpholin-4-yl-ethyl- amino)-methyl]-phenyl}- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 8c N-{4-[4-(3-Chloro-4- 229-231 467 0.18^(d)7.41 fluoro-phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-N′,N′- diethyl-ethane-1,2- diamine 8d (3-Chloro-4-fluoro-282-284 410 0.72^(d) 8.14 phenyl)-{6-[4-(iso- propylamino-methyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine^(a)Dichloromethane/ethanol 95:5 + 1% conc. ammonia^(b)Dichloromethane/ethanol 9:1 + 1% conc. ammonia^(c)Dichloromethane/ethanol 9:1 + 2% conc. ammonia^(d)Dichloromethane/ethanol 7:3 + 1% conc. ammonia

Example 9{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine

A mixture of 10.8 g (30 mmol)[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-aminein 450 ml DMF is treated with 6.8 ml (63 mmol) N-methylpiperazine and20.7 g (150 mmol) anhydrous potassium carbonate and the mixture heatedto 65° C. for 1 hour. The reaction mixture is cooled and the inorganicsalts removed by filtration (Hyflo Super Cel®; Fluka, Buchs,Switzerland). The DMF is evaporated under reduced pressure and theresidue purified through flash chromatography using firstdichloromethane/ethanol 9:1 and then dichloromethane/ethanol 9:1 plus 1%conc. ammonia. Crystallization of the pure fractions from THF (20 ml)and hexanes (80 ml) gives the title compound; m.p. 248-250° C.; MS-ES⁺:(M+H)⁺=427.

Step 9.14-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

1.8 g (6 mmol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acidethyl ester (WO 97/02266) are suspended in 40 ml n-butanol and treatedwith 1.5 ml (12 mmol) (R)-phenethylamine. The mixture is heated to 145°C. under stirring. After 3 h a clear brown solution is obtained which istreated with a second portion of (R)-phenethylamine (0.75 ml, 6 mmol).After stirring for additional 2 h the reaction mixture is cooled in anice bath and the title compound filtered and washed with cold n-butanoland ether; m.p. 288-290° C.; MS-ES⁺: (M+H)⁺=387.

Step 9.2{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

570 mg (15 mmol) lithium aluminum hydride are suspended in 150 ml dryTHF at RT. 1.23 g (3 mmol)4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester are added and the mixture heated to reflux for 1 h. Themixture is cooled in an ice bath and treated sequentially with water(0.57 ml), 15% sodium hydroxide solution (0.57 ml) and water (1.71 ml).The solid aluminum complex is removed by filtration (Hyflo Super Cel®;Fluka, Buchs, Switzerland), the filtrate dried over sodium sulfateevaporated. The residue is suspended in water, filtered and dried togive the title compound; m.p.>300° C.; R_(f)(dichloromethane/ethanol 9:1plus 1% conc. ammonia)=0.43; HPLC t_(R)=8.71 min.

Step 9.3[6-(4-Chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

A solution of thionyl chloride (25.7 ml, 0.328 mol) in 180 ml of tolueneis cooled to −10° C. Solid{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol(11.3 g, 0.0328 mol) is added in 8 portions over a range of 1 h. Thetemperature is then increased slowly to 0° C. and the mixture stirredfor 2 h. The cold reaction mixture is filtered and the solid washed withtoluene and ether. The crude product is suspended in water and treatedwith saturated sodium bicarbonate solution until the mixture turnsbasic. The mixture is stirred well for about 10 min and filtered. Thesolid is thoroughly washed with water and dried under reduced pressureto give the title compound; m.p.>320° C.; R_(f)(dichloromethane/ethanol9:1)=0.46; HPLC t_(R)=10.63 min; MS-ES⁺: (M+H)⁺=363.

Examples 10-16q

The following Examples are synthesized from[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineusing an analogous procedure described in Example 9

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 10 [6-(4-Diethylamino- 246-248 400 0.5^(a) 7.96 methyl-phenyl)-7H-pyrrolo[2,3-d]- pyrimidin-4-yl]-((R)-1- phenyl-ethyl)-amine 11{6-[4-(4-Ethyl-piperazin- 245-247 441 0.38^(a) 7.141-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-yl}-((R)-1-phenyl-ethyl)-amine 12 ((R)-1-Phenyl-ethyl)-[6- 254-256 398 0.5^(a) 7.91(4-pyrrolidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 13 [6-(4-Dimethylamino- 241-243 427 0.39^(a)6.35 methyl-phenyl)-7H- pyrrolo[2,3-d]- pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine 14 ((R)-1-Phenyl-ethyl)-[6- 246-248 412 0.53^(a) 8.1(4-piperidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-yl]-amine 15 [6-(4-Morpholin-4- 263-265 414 0.6^(a) 7.5ylmethyl-phenyl)-7H- pyrrolo[2,3-d]- pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine 16 {6-[4-(3,5-Dimethyl- 208-210 441 0.3^(a) 7.16piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)- amine 16a (6-{4-[(2-Morpholin-4- 222-224 4570.46^(b) 6.66 yl-ethylamino)-methyl]- phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- ((R)-1-phenyl-ethyl)- amine 16b((R)-1-Phenyl-ethyl)-(6- 253-255 428 0.42^(c) 7.18{4-[(tetrahydro-pyran- 4-ylamino)-methyl]- phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 16c N,N-Diethyl-N′-{4-[4- 145-150 443 0.55^(b)6.73 ((R)-1-phenyl-ethyl- amino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-ethane-1,2- diamine 16d {6-[4-(tert-Butylamino- >300 4000.53^(c) 7.68 methyl)-phenyl]-7H- pyrrolo[2,3-d]- pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 16e {6-[4-(isopropylamino- 266-268 386 0.5^(c)7.66 methyl)-phenyl]-7H- pyrrolo[2,3-d]- pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 16f [6-(4-Ethylaminomethyl- 236-238 372 0.33^(c)7.41 phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]- ((R)-1-phenyl-ethyl)-amine 16g [6-(4-Methylamino- 234-236 358 0.1^(c) 7.27 methyl-phenyl)-7H-pyrrolo[2,3-d]- pyrimidin-4-yl]-((R)- 1-phenyl-ethyl)-amine^(a)Dichloromethane/ethanol 9:1 + 1% conc. ammonia^(b)Dichloromethane/ethanol 7:3 + 2% conc. ammonia^(c)Dichloromethane/ethanol 9:1 + 2% conc. ammonia

Example 17(4-Benzyloxy-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

A mixture of 220 mg (0.5 mmol) crude(4-benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminein 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33%solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) andthen heated under reflux for 1 h. The resulting solution is cooled andthe solvent evaporated. The residue is dissolved in a mixture ofdichloromethane and ethanol (95:5), washed with water, dried over sodiumsulfate and the solvent evaporated. The solid material is then suspendedin ether stirred for 5 min and filtered. Purification of the crudematerial through flash chromatography using dichloromethane/ethanol 9:1plus 1% conc. ammonia gives the title compound; m.p. 272-274° C.;MS-ES⁺: (M+H)⁺=450.

Step 17.1(4-Benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

This material is prepared in an analogous procedure as described insteps 1.1 to 1.3; m.p.>300° C.; HPLC t_(R)=12.19 min; MS-ES⁺:(M+H)⁺=441.

Examples 18-24

The following Examples are synthesized from(4-benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineusing an analogous procedure described in Example 17:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 18 (4-Benzyloxy-phenyl)- 256-258 505 0.28^(a) 8.37{6-[4-(4-methyl- piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine 19 (4-Benzyloxy-phenyl)-[6- 256-258 490 0.5^(b)9.4 (4-piperidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 20 (4-Benzyloxy-phenyl)-[6- 272-274 492 0.25^(b)9.03 (4-morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 21 (4-Benzyloxy-phenyl)-[6- 271-273 478 0.15^(a)9.30 (4-diethylaminomethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 22 (4-Benzyloxy-phenyl)- 256-258 519 0.6^(b)8.37 {6-[4-(4-ethyl-piperazin- 1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]-pyrimidin-4-yl}-amine 23 (4-Benzyloxy-phenyl)-[6- 265-267 476 0.44^(b)9.23 (4-pyrrolidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 24 (4-Benzyloxy-phenyl)- 269-271 519 0.3^(b)8.32 {6-[4-(3,5-dimethyl- piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine ^(a)Dichloromethane/ethanol 95:5 + 1% conc.ammonia ^(b)Dichloromethane/ethanol 9:1 + 1% conc. ammonia

Example 25[6-(3-Dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

A mixture of 240 mg (0.5 mmol) crude[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-aminein 15 ml ethanol is treated with 0.8 ml (5 mmol) of a 33% solution ofdimethylamine in ethanol (Fluka, Buchs, Switzerland) and then heatedunder reflux for 1 h. The clear solution is cooled and the solventevaporated. The residue is purified with flash chromatography usingdichloromethane/ethanol 95:5 and then dichloromethane/ethanol 9:1 plus1% conc. ammonia to give the title compound; m.p. 108-110° C.; MS-ES⁺:(M+H)⁺=372.

Step 25.1{3-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

This material is prepared in an analogous procedure as described insteps 9.1 to 9.2; m.p. 217-219° C.; MS-ES⁺: (M+H)⁺=345.

Step 25.2[6-(3-Chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

A mixture of 688 mg (2 mmol){3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanoland 578 mg (2.2 mmol) triphenylphosphine in 60 ml dichloromethane istreated at 0° C. with 293 mg (2.2 mmol) N-chlorosuccinimide. Afterstirring 1 h at 0° C. all the material has gone into solution. Thesolvent is evaporated and the title compound purified with flashchromatography using dichloromethane/ethanol 95:5 (the title compound iscontaminated with a small amount of triphenylphosphine oxide); R_(f)(dichloromethane/ethanol 95:5)=0.35; MS-ES⁺: (M+H)⁺=363.

Examples 26-32

The following Examples are synthesized from[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineusing an analogous procedure as described in Example 25:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 26 [6-(3-Diethylamino- 110-113 400 0.6^(a) 8.15 methyl-phenyl)-7H-pyrrolo[2,3-d]- pyrimidin-4-yl]-((R)- 1-phenyl-ethyl)-amine 27{6-[3-(4-Ethyl-piperazin- 128-130 441 0.34^(b) 7.31-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-yl}-((R)-1-phenyl-ethyl)-amine 28 ((R)-1-Phenyl-ethyl)-[6- 90-92 398 0.50^(b) 7.97(3-pyrrolidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 29 {6-[3-(4-Methyl- 112-115 427 0.27^(b) 7.25piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine 30 ((R)-1-Phenyl-ethyl)-[6- 108-110 412 0.6^(b)8.19 (3-piperidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 31 [6-(3-Morpholin-4- 242-243 414 0.28^(a) 7.8ylmethyl-phenyl)-7H- pyrrolo[2,3-d]- pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine 32 {6-[3-(3,5-Dimethyl- 128-130 441 0.3^(b) 7.18piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine ^(a)Dichloromethane/ethanol 95:5 + 1% conc.ammonia ^(b)Dichloromethane/ethanol 9:1 + 1% conc. ammonia

Example 33(3-Chloro-4-fluoro-phenyl)-[6-(3-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

The title compound is synthesized analogously to Example 1 starting with(3-chloro-4-fluoro-phenyl)-[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;m.p. 218-220° C.; MS-ES⁺: (M+H)⁺=396.

Step 33.1(3-Chloro-4-fluoro-phenyl)-[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

The title compound is prepared in an analogous procedure as described insteps 1.1 to 1.3; R_(f) (dichloromethane/ethanol 95:5 plus 1% conc.ammonia)=0.45; MS-ES⁺: (M+H)⁺=387.

Examples 34-39

The following Examples are synthesized from(3-chloro-4-fluoro-phenyl)-[6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineusing an analogous procedure as described in Example 33:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 34 (3-Chloro-4-fluoro- 210-212 424 0.32^(a) 8.76phenyl)-[6-(3-diethyl- aminomethyl-phenyl)- 7H-pyrrolo[2,3-d]-pyrimidin-4-yl]-amine 35 (3-Chloro-4-fluoro- 238-240 465 0.4^(b) 7.7phenyl)-{6-[3-(4- ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]- pyrimidin-4-yl}-amine 36 (3-Chloro-4-fluoro- 238-240 4220.45^(b) 8.44 phenyl)-[6-(3-pyrrolidin- 1-ylmethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 37 (3-Chloro-4-fluoro- 221-223451 0.33^(b) 7.6 phenyl)-{6-[3- (4-methyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-yl}-amine 38(3-Chloro-4-fluoro- 233-235 436 0.45^(b) 8.75 phenyl)-[6-(3-piperidin-1-ylmethyl-phenyl)- 7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 39(3-Chloro-4-fluoro- 290-292 438 0.21^(a) 8.15 phenyl)-[6-(3-morpholin-4-ylmethyl-phenyl)- 7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine^(a)Dichloromethane/ethanol 95:5 + 1% conc. ammonia^(b)Dichloromethane/ethanol 9:1 + 1% conc. ammonia

Example 40N-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-piperidin-1-yl-acetamide

A mixture of 80 mg (0.19 mmol)2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamidein 1.5 ml n-butanol is treated with 47 μl (0.48 mmol) piperidine andthen heated to 100° C. for 2 h. The clear solution is cooled and thesolvent evaporated. The residue is purified with flash chromatographyusing a mixture of ethyl acetate/methanol with increasing concentrationsof methanol starting with 100:2.5 and ending with 10:1. The titlecompound is obtained as a colorless powder; m.p. 194-196° C.; MS-ES⁺:(M+H)⁺=469.

Step 40.1 2-Amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethylester

A mixture of 42.53 g (0.255 mol) carbamimidoyl-acetic acid ethyl esterhydrochloride in 70 ml absolute ethanol is treated at 0 to 5° C. with95.3 ml of a 21% sodium ethoxide solution in ethanol (0.255 mol) andstirred 5 min at 0 to 5° C. 4-Bromoacetyl-benzonitrile (28.6 g, 0.128mol) is then added in portions over 20 min at 0 to 5° C. Stirring iscontinued at this temperature for 5 min then the ice bath is removed andthe yellow suspension is stirred over night at RT. The solid is filteredoff, washed with ethanol and ether and re-suspended in 450 mlactonitrile. The mixture is heated for 5 min under reflux, filteredwhile still hot and then cooled in an ice bath. The title compound iscollected by succion and dried. Flash chromatography(dichloromethane/ethyl acetate mixture) of the mother liquors gives anadditional crop of the title compound as a yellow solid; m.p. 228-229°C.; MS-ES⁺: (M+H)⁺=254.

Step 40.2 4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile

A mixture of 36.6 g (0.143 mol)2-amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester, 140ml DMF, 305 ml formamide and 14.6 ml 85% formic acid is heated for 16 hat 150° C. The resulting yellow suspension is cooled to 10° C. andfiltered. The solid is washed with methanol (120 ml) and ether (150 ml)and dried. The title compound is obtained as yellowish crystals;m.p.>410° C.; MS-ES⁺: (M+H)⁺=254.

Step 40.3 4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile

4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile (2.36 g, 0.01mol) are suspended in 40 ml acetonitril and 4.99 ml (0.02 mol) 4 Nhydrochloric acid solution in dioxane. After addition of 3.66 ml (0.04mol) phosphorus oxichloride the mixture is heated under reflux for 3days. The solid is filtered off and the mother liquor evaporated. Theresidue and the solid are dissolved in 30 ml DMF at 60° C. and 25 ml ofa conc. sodium bicarbonate solution and 25 ml water are added and theresulting suspension cooled, filtered and the solid washed with water.The title compound is dried at 100° C. for 6 h under reduced pressure;m.p. 296-297° C.; HPLC t_(R)=11.59 min.

Step 40.44-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrile

A mixture of 1.27 g (5 mmol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile, 1.4 ml (10mol) triethylamine and 0.955 ml (7.5 mmol) R(+)-1-phenyl-ethylamine in25 ml dioxane is heated under reflux for 24 h. A second portion ofR(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) is added and heating iscontinued for 24 h. After addition of a third portion ofR(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) and additional 24 h thereaction mixture is cooled to 10° C. and the title compound filtered offand washed with dioxane. From the mother liquor a second crop isobtained after concentration of the solution; m.p. 333-336° C.; MS-ES⁺:(M+H)⁺=340.

Step 40.5[6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

Raney-Nickel (0.1 g) catalyzed hydrogenation of 0.206 g (0.6 mmol)4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrilein a mixture of 5% ammonia in methanol (20 ml) and THF (4 ml) for 6 h atatmospheric pressure followed by filtration and evaporation of thesolvent gives the title compound; m.p. 253-256° C.; MS-ES⁺: (M+H)⁺=344.

Step 40.62-Chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

A mixture of 0.21 g (0.6 mmol)[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineand 94 μl (0.67 mmol) triethylamine in 5 ml dry THF is treated dropwisewith a solution of chloro-acetyl chloride (51 μl, 0.64 mmol) in 0.5 mlof dry THF at RT. After stirring for 30 min small amounts of insolublematerial is removed by filtration and the filtrate is evaporated. Theresidue is purified by flash chromatography using ethyl acetate/methanol100:2 to 100:4 as eluent. The title compound is obtained as light brownsolid; HPLC t_(R)=9.36 min; MS-ES⁺: (M+H)⁺=420.

Examples 41-45

The following Examples are synthesized from2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamideusing an analogous procedure as described in Example 40:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 41 N-{4-[4-((R)-1-Phenyl- 196-198 455 0.25^(a) 7.92ethylamino)-7H-pyrrolo- [2,3-d]pyrimidin-6- yl]-benzyl}-2-pyrrolidin-1-yl-acetamide 42 2-Morpholin-4-yl-N-{4- 199-202 471 0.28^(a)7.78 [4-((R)-1-phenyl-ethyl- amino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-acetamide 43 2-(4-Methyl-piperazin-1- 150-152 484 0.29^(b) 7.45yl)-N-{4-[4-((R)- 1-phenyl-ethylamino)- 7H-pyrrolo[2,3-d]-pyrimidin-6-yl]-benzyl}- acetamide 44 2-Dimethylamino-N-{4- 263-266 4290.21^(a) 7.64 [4-((R)-1-phenyl-ethyl- amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- benzyl}-acetamide 45 2-(4-Ethyl-piperazin-1- 121-124498 0.26^(b) 7.66 yl)-N-{4-[4-((R)-1- phenyl-ethylamino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]- benzyl}-acetamide^(a)dichloromethane/methanol 9:1 ^(b)dichloromethane/methanol/conc.ammonia 90:10:1

Example 46N-{4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide

2-Chloro-N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(100 mg, 0.225 mmol) in 2 ml n-butanol and 0.12 ml (0.67 mmol) 5.6 Ndimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred andheated to 100° C. for 6 h. The mixture is cooled, filtered and the solidre-suspended in 3 ml hot ethanol. After cooling the title compound iscollected by filtration, washed with ethanol and dried; m.p. 278-282;R_(f)(ethyl acetate/methanol 8:2)=0.14; HPLC t_(R)=8.04 min; MS-ES⁺:(M+H)⁺=453.

Step 46.12-Chloro-N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

This compound is synthesized using an analogous sequence as describedfor2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(steps 40.4 to 40.6); m.p. 320-325° C.;R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.39; MS-ES⁺:(M+H)⁺=444.

Examples 47-50

The following Examples are synthesized from2-chloro-N-{4-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamideusing an analogous procedure as described in Example 46:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 47 N-{4-[4-(3-Chloro-4- 245-247 522 0.53^(a) 8.04fluoro-phenylamino)-7H- pyrrolo[2,3-d]- pyrimidin-6-yl]-benzyl}-2-(4-ethyl- piperazin-1-yl)-acetamide 48 N-{4-[4-(3-Chloro-4-272-275 495 0.48^(b) 8.19 fluoro-phenylamino)-7H- pyrrolo[2,3-d]-pyrimidin-6-yl]-benzyl}- 2-morpholin-4-yl- acetamide 49N-{4-[4-(3-Chloro-4- 229-232 495 0.48^(a) 8.52 fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin- 6-yl]-benzyl}-2- piperidin-1-yl-acetamide 50N-{4-[4-(3-Chloro-4- 246-249 508 0.61^(a) 7.93 fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin- 6-yl]-benzyl}-2-(4- methyl-piperazin-1-yl)-acetamide ^(a)dichloromethane/methanol/conc. ammonia 40:10:1 ^(b)ethylacetate/methanol 8:2

Example 51N-{4-[4-(4-Benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide

N-{4-[4-(4-Benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-chloro-acetamide(0.2 g, 0.4 mmol) in 3 ml n-butanol and 0.215 ml (1.2 mmol) 5.6 Ndimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred andheated to 100° C. for 6 h. After addition of a second portion ofdimethylamine solution (0.3 ml, 1.68 mmol) the mixture is heated for 6more hours. The mixture is then cooled, filtered and the solidre-suspended in 3 ml warm dichloromethane/methanol 2:1. After coolingthe title compound is collected by filtration and purified further withflash chromatography using a gradient of dichloromethane/methanol100:2.5 to 10:1; m.p. 233-235; MS-ES⁺: (M+H)⁺=507.

Step 51.1N-{4-[4-(4-Benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2chloro-acetamide

This compound is synthesized using an analogous sequence as describedfor2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(steps 40.4 to 40.6); R_(f)(dichloromethane/methanol/conc. ammonia90:10:1)=0.40; MS-ES⁺: (M+H)⁺=498.

Examples 52-53

The following Examples are synthesized fromN-{4-[4-(4-benzyloxy-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-chloro-acetamideusing an analogous procedure as described in Example 51:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 52 N-{4-[4-(4-Benzyloxy- 232-234 562 0.18^(a) 8.69phenylamino)-7H- pyrrolo[2,3-d]- pyrimidin-6-yl]-benzyl}-2-(4-methyl-piperazin- 1-yl)-acetamide 53 N-{4-[4-(4-Benzyloxy- 246-248547 0.42^(b) 9.31 phenylamino)-7H- pyrrolo[2,3-d]-pyrimidin-6-yl]-benzyl}- 2-piperidin-1-yl- acetamide^(a)dichloromethane/methanol/conc. ammonia 90:10:1^(b)dichloromethane/methanol 85:15

Example 54N-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-3-piperidin-1-yl-propionamide

Under an atmosphere of nitrogen a mixture of 0.0865 g (0.55 mmol)3-piperidin-1-yl-propionic acid and 0.117 ml (0.68 mmol)N,N-diisopropylethylamine in DMF (5 ml) is treated at RT and over aperiod of 5 min with a solution of 0.163 g (0.55 mmol)O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate(TPTU, Fluka, Buchs, Switzerland) in 2 ml DMF. After stirring for 5 minthe resulting solution is added slowly (1.5 h) at RT to 0.172 g (0.5mmol)[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(step 40.5) in 3 ml DMF. The reaction mixture is allowed to stand overnight after which the DMF is evaporated under reduced pressure. Theresidue is purified by flash chromatography using gradients of firstdichloromethane/methanol 100:2.5 to 10:1 and then mixtures ofdichloromethane/methanol/conc. ammonia 90:10:0.5 to 40:10:1. The titlecompound is obtained as yellowish solid; m.p. 140° C.; MS-ES⁺:(M+H)⁺=483.

As a second product of this reactionN-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acrylamideis obtained; m.p. 249-250° C.; MS-ES⁺: (M+H)⁺=398.

Examples 55-57

The following Examples are synthesized from[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(step 40.5) using an analogous procedure as described in Example 54:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 55 3-Diethylamino-N-{4- 175-177 471 0.19^(a) 8.11[4-((R)-1-phenyl-ethyl- amino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-propionamide 56 4-Dimethylamino-N-{4- 195-203 457 0.04^(a) 7.76[4-((R)-1-phenyl-ethyl- amino)-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}-butyramide 57 Pyridine-2-carboxylic 221-223 449 0.51^(a) 10.16acid 4-[4-((R)-1-phenyl- ethylamino)-7H- pyrrolo[2,3-d]-pyrimidin-6-yl]- benzylamide ^(a)dichloromethane/methanol/conc. ammonia90:10:1

Example 58N-{4-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-3-diethylamino-propionamide

The title compound is synthesized from[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-chloro-4-fluoro-phenyl)-amineusing an analogous procedure as described in Example 54. In this caseactivation of the carboxylic acid is done with(benzotriazole-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoroborate(BOP, Fluka, Buchs, Switzerland) and N-methylmorpholin; m.p. 229-232;HPLC t_(R)=8.52 min; MS-ES⁺: (M+H)⁺=495.

Step 58.1[6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-chloro-4-fluoro-phenyl)-amine

The title compound is synthesized using an analogous procedure asdescribed in steps 40.4 to 40.5; m.p. 350-351; MS-ES⁺: (M+H)⁺=368.

Examples 59-61

The following Examples are synthesized from[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(3-chloro-4-fluoro-phenyl)-amine(step 58.1) using an analogous procedure as described in Example 58:

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min] 59 Pyridine-2-carboxylic 340-342 473 — 10.62 acid4-[4-(3-chloro-4- fluoro-phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzylamide 60 N-{4-[4-(3-Chloro-4- 272-273 481 0.31^(a) 8.15fluoro-phenylamino)-7H- pyrrolo[2,3-d]pyrimidin- 6-yl]-benzyl}-4-dimethyl-amino- butyramide 61 N-{4-[4-(3-Chloro-4- 230-235 507 0.76^(a)8.66 fluoro-phenylamino)-7H- pyrrolo[2,3-d]pyrimidin- 6-yl]-benzyl}-3-piperidin-1-yl- propionamide ^(a)dichloromethane/methanol/conc. ammonia40:10:1

Example 622-Dimethylamino-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

A mixture of 210 mg (0.5 mmol)2-chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamidein 3 ml dry dioxane is treated with 268 μl (1.5 mmol) of a 5.6 Ndimethylamine solution in ethanol (Fluka, Buchs, Switzerland) and thenheated to 100° C. for 6 h. The clear yellow solution is cooled and thesolvent evaporated. The residue is purified by flash chromatographyusing a mixture of dichloromethane/methanol with gradually increasingconcentrations of methanol starting with 100:2.5 and ending with 100:5and then switching to dichloromethane/methanol/conc. ammonia startingwith 100:5:0.25 and ending with 100:10:0.5. The title compound isobtained as a colorless foam; R_(f)(dichloromethane/methanol/conc.ammonia 90:10:1)=0.41; MS-ES⁺: (M+H)⁺=429.

Step 62.12-Chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

The title compound is synthesized using an analogous procedure asdescribed in steps 40.1 to 40.6; m.p. 300-310 (decomposition);R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.54; MS-ES⁺:(M+H)⁺=420.

Example 632-(4-Methyl-piperazin-1-yl)-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

The title compound is obtained as a tan resin using an analogousprocedure as described in Example 62;R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.20; HPLCt_(R)=7.77 min; MS-ES⁺: (M+H)⁺=484.

Example 64N-{3-[4-(3-Chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2-dimethylamino-acetamide

2-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(120 mg, 0.222 mmol) in 2 ml dioxane and 0.145 ml (0.81 mmol) 5.6 Ndimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred andheated to 100° C. for 4.5 h. The mixture is cooled and the solventevaporated. The residue is shaken with THF (5 ml), dichloromethane (3ml), methanol (2 ml) and saturated sodium bicarbonate (2 ml). The twoclear layers are separated and the organic phase is treated with 1 gsilica gel. The solution containing the silica gel is evaporated and thesolid put on top of a flash chromatography column containing 33 g ofsilica gel. The column is eluted using a mixture ofdichloromethane/methanol with gradually increasing concentrations ofmethanol starting with 100:2.5 and ending with 100:5 and then switchingto dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 andending with 100:10:0.5. The title compound is obtained as colorlesscrystals; m.p. 272-273° C.; MS-ES⁺: (M+H)⁺=453.

Step 64.12-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide

The title compound is synthesized using an analogous procedure asdescribed in steps 40.1 to 40.6; R_(f)(dichloromethane/methanol/conc.ammonia 90:10:1)=0.47; HPLC t_(R)=9.98 min; MS-ES⁺: (M+H)⁺=444.

Examples 65-66

The following Examples are synthesized from2-chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide(step 64.1) using an analogous procedure as described in Example 64:

Exam- ple m.p. MS-ES⁺: TLC^(a) HPLC Number Name [° C.] (M + H)⁺ R_(f)t_(R) [min] 65 N-{3-[4-(3-Chloro-4- 214-214 508 0.21 8.08fluoro-phenylamino)-7H- pyrrolo[2,3-d]pyrimidin- 6-yl]-benzyl}-2-(4-methyl-piperazin-1-yl)- acetamide 66 N-{3-[4-(3-Chloro-4- 252-254 4930.53 8.65 fluoro-phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-2- piperidin-1-yl-acetamide^(a)Dichloromethane/methanol/conc. ammonia 90:10:1

Examples 67-78

The following Examples are synthesized using an analogous procedure asdescribed in Example 1. However, a modified protocol is applied for thepreparation of the intermediates: Instead of reducing the ethyl-esterwith lithium aluminum hydride in THF (as described in step 1.2), the4-hydroxymethyl derivatives are prepared by reduction withdiisobutyl-aluminium hydride in a 1:1 mixture of dichloromethane anddioxane at ambient temperature (Examples 67-72 and 76-78). For preparingthe intermediates of Examples 73-75, reduction of4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl esterwith diisobutyl-aluminium hydride in THF at ambient temperature yields[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol (see step108.3). Substitution of the chlorine by 2-methoxy-5-amino-phenol asdescribed in step 1.1 then gives5-[6-(4-hydroxymethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methoxy-phenol.

Exam- ple m.p. MS-ES⁺: TLC HPLC^(a) Number Name [° C.] (M + H)⁺ R_(f)t_(R) [min] 67 2-Methyl-5-{6-[3-(4- 256-258 429 0.14^(b) 6.8methyl-piperazin-1- ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol 68 5-[6-(3-Dimethylamino- 258-260 374 0.21^(b) 7.2methyl-phenyl)-7H- pyrrolo-[2,3-d]pyrimidin- 4-ylamino]-2-methyl- phenol69 2-Methoxy-5-{6-[3-(4- 251-252 445 0.16^(b) 6.1 methyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-ylamino}-phenol 705-[6-(3-Dimethylamino- 250-251 390 0.17^(b) 6.8 methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino]-2- methoxy-phenol 715-[6-(4-Dimethylamino- 374 0.31^(b) 7.2 methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino]-2-methyl- phenol 722-Methyl-5-{6-[4-(4- >300 429 6.9 methyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-ylamino}-phenol 735-[6-(4-Dimethylamino- methyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methoxy- phenol 74 2-Methoxy-5-{6-[4-(4- 445 0.19^(d) 6.3methyl-piperazin-1- ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-phenol 75 2-Methoxy-5-[6-(4- morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4- ylamino]-phenol 76[(R)-1-(4-Chloro- 273-274 406 0.32^(b) 9.1 phenyl)-ethyl]-[6-(4-dimethylaminomethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 77[(R)-1-(4-Chloro- 232-233 461 0.31^(b) 8.6 phenyl)-ethyl]-{6-[4-(4-methyl-piperazin-1- ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-amine 78 [(R)-1-(4-Chloro- 448 0.16^(c) 9.2 phenyl)-ethyl]-[6-(4-morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine^(a)HPLC: Column: (250 × 4.6 mm) packed with reversed-phase materialC18-Nucleosil (5 μm mean particle size, with silica gel covalentlyderivatized with octadecylsilanes, Macherey & Nagel, Düren, Germany).Detection by UV absorption at 215 nm. The retention times (t_(R)) aregiven in minutes. Flow rate: 1 ml/min. Gradient: 20% → 100% a) in b) for13 min + 5 min 100% a). a): Acetonitrile + 0.05% TFA; b): water + 0.05%TFA. ^(b)Dichloromethane/ethanol 4:1 + drop of conc. ammonia^(c)EtOAc/ethanol 9:1 ^(d)THF/methanol 9:1 + drop of conc. Ammonia

Example 79(3-Chloro-phenyl)-[6-(4-dimethylaminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-aminehydrochloride

Lithium aluminum hydride (72 mg, 1.9 mmol) is suspended in dry THF (12ml) under a nitrogen atmosphere. Solid4-[4-(3-chloro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-N,N-dimethyl-benzamide(described in WO 97/02266, 140 mg, 0.37 mmol) is added and the mixtureheated to 60° C. for 1 h. The reaction mixture is then hydrolized at 0°C. by sequential addition of water (0.072 ml), 15% sodium hydroxide(0.072 ml) and water (0.21 ml). The precipitate is removed by filtrationand the filtrate concentrated on a rotary evaporator. The yellowcrystalline residue is suspended in methanol, filtered, suspended intoluene, filtered, suspended in methanol again and filtered to give thefree base of the title compound [R_(f)(dichloromethane/methanol 9:1 plus1 drop of conc. ammonia)=0.36]. This is suspended in methanol (2 ml) andtreated with 1 N hydrochloric acid (0.2 ml). The suspension is stirredwell and filtered. The crystals are triturated in methanol/water 9:1 andfiltered again to give the title compound; m.p. 280-283° C.; MS-ES⁺:(M+H)⁺=378.

Examples 80-81

The following Examples are synthesized from the corresponding amides (WO97/02266) using an analogous procedure as described in Example 79:

Exam- ple m.p. MS-ES⁺: TLC^(a) HPLC Number Name [° C.] (M + H)⁺ R_(f)t_(R) [min] 80 (3-Chloro-phenyl)-{6-[4- 227-229 433 0.35 6.74(4-methyl-piperazin-1- ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-amine dihydrochloride 81 (3-Chloro-phenyl)-[6-(4- 278-280 420 0.497.25 morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine hydrochloride ^(a)of the free base using dichloromethane/methanol9:1 plus 1 drop of conc. ammonia

Example 822-((2-Hydroxy-ethyl)-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-amino)-ethanol

[6-(4-Aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(step 40.5, 0.5 g, 1.46 mmol) is dissolved in THF (7.5 ml) and water(0.75 ml) and cooled to −10° C. A stream of ethylene oxide is thenpassed through the solution for about 40 min (amount of ethylene oxideabsorbed 5 to 6 g). The flask is sealed and the mixture stirred at 0° C.for 30 min and then at 50° C. for 16 h. The clear yellow solution iscooled and the solvents evaporated. The residue is purified by flashchromatography on 34 g of silica gel. The column is eluted using amixture of dichloromethane/methanol with gradually increasingconcentrations of methanol starting with 100:1.25 and ending with100:2.5 and then switching to dichloromethane/methanol/conc. ammoniastarting with 100:2.5:0.125 and ending with 100:10:0.5. Fractionscontaining the title compound were pooled and concentrated on a rotaryevaporator. The residue is taken up in a small amount of dichloromethaneand the resulting solid collected by filtration; m.p. 194-197° C.; R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.21; MS-ES⁺:(M+H)⁺=432.

Example 83(3-Chloro-benzyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

(3-Chloro-benzyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine(150 mg, 0.35 mmol) is suspended in 5 ml dioxane and treated withN-ethyl-piperazine. The mixture is heated to 90° C. for 7 h. The solventis evaporated and the residue is purified by flash chromatography on 34g of silica gel. The column is eluted using a mixture ofdichloromethane/methanol with gradually increasing concentrations ofmethanol starting with 100:1.25 and ending with 100:5 and then switchingto dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 andending with 100:10:0.5. Fractions containing the title compound werepooled and concentrated on a rotary evaporator to give the titlecompound; m.p. 241-243° C.; MS-ES⁺: (M+H)⁺=461.

Step 83.14-[4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

This compound is synthesized following an analogous procedure asdescribed in Example 1, step 1.1 starting from4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) and 3-chloro-benzylamine; m.p. 305-306° C.; MS-ES⁺:(M+H)⁺=407.

Step 83.2{4-[(4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

2.236 g (0.059 mol) lithium aluminum hydride are suspended in 600 ml dryTHF at RT.4-[4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester (4.8 g, 0.0118 mol) is added in portions over 5 min andthe resulting mixture is heated to 60° C. for 1 h. The mixture is cooledin an ice bath to about 10° C. and treated sequentially with THF/water1:1 (2.24 ml), 15% sodium hydroxide solution (4.48 ml) and water (6.72ml). The solid aluminum complex is removed by filtration (Hyflo SuperCel®; Fluka, Buchs, Switzerland) and washed thoroughly with THF. Thefiltrate is concentrated to about 50 ml and the resulting suspensiontreated with water/ethanol 9:1 (50 ml). After stirring for 10 min thecrystals were collected by filtration and dried under reduced pressureto give the title compound; m.p. 296-298° C.; MS-ES⁺: (M+H)⁺=365.

Step 83.3(3-Chloro-benzyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

A solution of 0.79 ml (10 mmol) thionylchloride in 5.5 ml of toluene iscooled to −10° C. Solid{4-[4-(3-chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolis added and the suspension stirred at 0° C. for 2 h and then at RT for17 h. The solid is filtered off, washed with toluene and suspended inwater (3 ml). The mixture is treated with saturated sodium bicarbonatesolution (3 ml) and stirred for 10 min. The crystals are collected byfiltration washed with water, a small amount of ethanol and ether anddried to give the title compound; m.p. decomposition ˜300° C.;R_(f)(dichloromethane/methanol/conc. ammonia 90:10:1)=0.61; MS-ES⁺:(M+H)⁺=383.

Examples 84-107i

The following Examples are synthesized using an analogous procedure asdescribed in

Example 83

Exam- ple m.p. MS-ES⁺: TLC HPLC Number Name [° C.] (M + H)⁺ R_(f) t_(R)[min]  84 (3-Chloro-benzyl)-[6-(4- 219-222 393 — 7.46dimethylaminomethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine  85(3-Chloro-benzyl)-[6-(4- 234-235 432 0.44^(a) 7.95 piperidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine  86(3-Chloro-benzyl)-[6-(4- 253-  434 — 7.55 morpholin-4-ylmethyl- 254.5phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine  87(3-Chloro-benzyl)-[6-(4- 231-233 420 0.35^(a) 7.86 diethylaminomethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine  88(3-Chloro-benzyl)-[6-(4- 222-225 418 0.32^(a) 7.77pyrrolidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 89 (3-Chloro-benzyl)-{6-[4- 235-237 447 0.34^(a) 6.99(4-methyl-piperazin-1- ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]-pyrimidin-4-yl}-amine  90 (2-Chloro-benzyl)-[6-(4- 256-258 392 0.30^(a)7.65 dimethylaminomethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine  91 (2-Chloro-benzyl)-{6-[4- 255-256 4610.23^(a) 7.37 (4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl}-amine  92 (2-Chloro-benzyl)-[6-(4-262-264 432 0.54^(a) 7.77 piperidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine  93 (2-Chloro-benzyl)-[6-(4- 276-279 434 0.427.39 morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine  94 (2-Chloro-benzyl)-{6-[4- 267-269 4470.37^(a) 6.80 (4-methyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]- pyrimidin-4-yl}-amine  95 (2-Chloro-benzyl)-[6-(4-264-265 418 0.33^(a) 7.59 pyrrolidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine  96 (2-Chloro-benzyl)-[6-(4- 257-258 4200.42^(a) 7.69 diethylaminomethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine  97 (2,5-Dichloro-benzyl)- 249-251 495 0.30^(a)7.44 {6-[4-(4-ethyl- piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine  98 (2,5-Dichloro-benzyl)-[6- 254-257 4260.30^(a) 7.91 (4-dimethylaminomethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine  99 (2,5-Dichloro-benzyl)-[6- 272-274 4680.42^(b) 7.97 (4-morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 100 (2,5-Dichloro-benzyl)-[6- 258-260 466 — 8.44(4-piperidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine101 (2,5-Dichloro-benzyl)-[6- 255-257 454 0.50^(c) 8.26(4-diethylaminomethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine102 (2,5-Dichloro-benzyl)- 244-246 481 0.37^(c) 7.43 {6-[4-(4-methyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine103 (2,5-Dichloro-benzyl)-[6- 266-268 452 0.48^(a) 8.20(4-pyrrolidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 104 [6-(4-Dimethylamino- 227-229 388 0.40^(d)6.91 methyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl]-(3-methoxy-benzyl)-amine 105 [6-(4-Diethylamino- 230-232 416 0.57^(d) 7.36methyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin- 4-yl]-(3-methoxy-benzyl)-amine 106 (3-Methoxy-benzyl)-[6- 220-222 414 0.50^(d) 7.29(4-pyrrolidin-1- ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-amine 107 (3-Methoxy-benzyl)-[6- 227-229 428 0.30^(e) 7.48(4-piperidin-1- ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-amine 107a (3-Methoxy-benzyl)-[6- 263-265 430 0.42^(f) 7.02(4-morpholin-4- ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-amine 107b (3-Methoxy-benzyl)-{6- 225-227 443 0.12^(f) 6.43[4-(4-methyl-piperazin- 1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-amine 107c {6-[4-(4-Ethyl-piperazin- 231-233 457 0.45^(f) 6.661-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-yl}-(3-methoxy-benzyl)-amine 107d (3-Methyl-benzyl)-[6-(4- 246-248 412 0.46^(f) 7.88piperidin-1-ylmethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine107e (3-Methyl-benzyl)-[6-(4- 259-261 414 0.37^(f) 7.74morpholin-4-ylmethyl- phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine107f [6-(4-Dimethylamino- 230-232 372 0.58^(d) 7.23 methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-(3-methyl- benzyl)-amine 107g[6-(4-Diethylamino- 241-243 400 0.6^(d) 7.71 methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-(3-methyl- benzyl)-amine 107h(3-Methyl-benzyl)-[6-(4- 241-243 398 0.5^(d) 7.63 pyrrolidin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-amine 107i(3-Methyl-benzyl)-{6-[4- 244-246 427 0.5^(d) 6.87 (4-methyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine 107j{6-[4-(4-Ethyl-piperazin- 250-252 441 0.4^(d) 6.91-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-yl}-(3-methyl-benzyl)-amine ^(a)Dichloromethane/methanol/conc. ammonia 90:10:1^(b)Dichloromethane/ethanol/conc. ammonia 92:8:1^(c)Dichloromethane/ethanol/conc. ammonia 93:7:1^(d)Dichloromethane/ethanol/conc. ammonia 90:10:1^(e)Dichloromethane/methanol 80:20 ^(f)Dichloromethane/methanol 80:20

Example 108Benzo[1,3]dioxol-5-yl-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

A mixture of 200 mg (0.53 mmol)benzo[1,3]dioxol-5-yl-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine,0.59 ml (5.3 mmol) 1-methyl-piperazine and a trace of NaI in 15 mlethanol is stirred for 4 h at 65° C. and 2 h at 80° C. underN₂-atmosphere. The orange solution is concentrated under vacuum and theresidue resolved with ethyl acetate and NaHCO₃-solution. The aqueouslayer is separated off and extracted twice with ethyl acetate. Theorganic phases are washed with water and brine, dried (MgSO₄) andpartially concentrated. Then the crystallized title compound can befiltered off; MS-ES⁺: (M+H)⁺=443; HPLC (conditions see Examples 67-78)t_(R)=7.1 min.

Step 108.1[4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol

To a suspension of 30.0 g (100 mmol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) in 450 ml dry THF at 10° C. under N₂-atmosphere, 500 mldiisobutyl-aluminium hydride (1 M in THF) were added dropwise. Theresulting clear solution is stirred for 1 h and then diluted with 2.1 lof dry THF. Then 98 ml of ethyl acetate are added, followed after 15 minby 45 ml of water and after 1 h by 22.5 ml of 4 N sodium hydroxide.After 1 h stirring, 200 g of Na₂SO₄ are added and stirring is continuedfor another hour. The mixture is filtered through Celite (Fluka, Buchs,Switzerland), the residue washed with THF and discarded. Concentrationof the filtrate to a volume of =0.1 l, addition of 0.3 l ofdichloromethane and filtration yields the title compound; Analysis forC₁₃H₁₀ClN₃O: calc. C 60.13%, H 3.88%, N 16.18%, Cl 13.65%; found C60.23%, H 4.03%, N 16.51%, Cl 13.28%.

Step 108.2{4-[4-(Benzo[1,3]dioxol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

A mixture of 1.5 g (5.8 mmol) of[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol and 1.58g (11.5 mmol) 3,4-methylendioxy-aniline in 30 ml n-butanol is stirredfor 16 h at 115° C. under N₂-atmosphere. After cooling to ambienttemperature, the title compound can be filtered off and washed withn-butanol; MS-ES⁺: (M+H)⁺=361; HPLC (conditions see Examples 67-78)t_(R)=8.7 min.

Step 108.3Benzo[1,3]dioxol-5-yl-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

To a suspension of 1.83 g of{4-[4-(benzo[1,3]dioxol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolin 56 ml of dioxane/acetonitrile 1:1 under N₂-atmosphere, 3.1 ml ofthionylchloride are added. After 16 h stirring, the suspension isdiluted with ethyl acetate and NaHCO₃-solution. The aqueous layer isseparated off and extracted twice with ethyl acetate. The organic phasesare washed with water and brine, dried (MgSO₄) and concentrated to yieldthe title compound; MS-ES⁺: (M+H)⁺=379; HPLC (conditions see Examples67-78) t_(R)=11.4 min.

Examples 108a-114

The following Examples are synthesized using an analogous procedure asdescribed in

Example 108

Exam- ple m.p. MS-ES⁺: TLC HPLC^(a) Number Name [° C.] (M + H)⁺ R_(f)t_(R) [min] 108a Benzo[1,3]dioxol-5-yl- 457 0.32^(c) 7.3{6-[4-(4-ethyl-piperazin- 1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl}-amine 109 Benzo[1,3]dioxol-5-yl- 3880.08^(b) 7.6 [6-(4-dimethylamino- methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-amine 110 Benzo[1,3]dioxol-5-yl- 4300.16^(b) 7.7 [6-(4-morpholin-4- ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-amine 111 (6-Methoxy-pyridin-3- 263-264417 0.78^(c) 7.2 yl)-[6-(4-morpholin-4- ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-amine 112 (6-Methoxy-pyridin-3- 241-242430 0.07^(b) 6.9 yl)-{6-[4-(4-methyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine 113(6-Methoxy-pyridin-3- 375 0.49^(c) 7.0 yl)-{6-[4-(dimethyl-amino-methyl)-phenyl]- 7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine 114(6-Methoxy-pyridin-3- 444 0.41^(c) 6.8 yl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine^(a)HPLC: conditions see Examples 67-78^(b)Dichloromethane/methanol/conc. ammonia 90:10:1^(c)THF/methanol/conc. ammonia 90:10:1

Example 1155-[6-(4-Morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1H-pyridin-2-one

To 84 mg (0.20 mmol) of(6-methoxy-pyridin-3-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineand 10 ml chloroform in an ampoule under N₂-atmosphere, 0.1 ml (0.73mmol) Me₃Sil is added. After stirring for 6 h at 70° C., diluted NaHCO₃solution and EtOAc is added to the suspension at RT. Stirring,filtration and washing with water yields the title compound; TLC(THF/methanol/conc. ammonia 90:10:1) R_(f)=0.23; MS-ES⁺: (M+H)⁺=403;HPLC (conditions see Examples 67-78) t_(R)=4.7 min.

Examples 116-118

The following Examples are synthesized using an analogous procedure asdescribed in Example 115 (eventually after purification withchromatography on SiO₂ or reversed phase medium pressure liquidchromatography: Nucleosil C₁₈, CH₃CN/H₂O+TFA):

Example MS-ES⁺: TLC HPLC^(a) Number Name (M + H)⁺ R_(f) t_(R) [min] 1165-[6-(4-Dimethylaminomethyl- 361 0.09^(d) 9.2^(b)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino]-1H- pyridin-2-one 1175-{6-[4-(4-Methyl-piperazin-1- 416 9.0^(c) ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-1H-pyridin-2-one 1185-{6-[4-(4-Ethyl-piperazin-1- 430 9.1^(c) ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-1H-pyridin-2-one ^(a)HPLC: solventsystem: a): Acetonitrile + 0.05% TFA; b): water + 0.05% TFA. ^(b)Grad:20% → 100% a) in b) for 13 min + 5 min 100% a). ^(c)Grad: 5% → 40% a) inb) for 9 min + 7 min 40% a). ^(d)THF/methanol/conc. ammonia 90:10:1

Example 119(6-Methoxy-pyridin-3-ylmethyl)-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine

(6-Methoxy-pyridin-3-ylmethyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine(400 mg, 1.05 mMol), 1.34 ml N-ethyl-piperazine and a trace of NaI isstirred for 2.5 h in 30 ml boiling ethanol. The solvent is evaporatedand the residue is re-dissolved in EtOAc and diluted NaHCO₃-solution.The separated aqueous layer is re-extracted with EtOAc and the organicphases are washed with water and brine, dried (Na₂SO₄) and partiallyconcentrated in vacuuo. The title compound crystallizes and can befiltered off; MS-ES⁺: (M+H)⁺=458; elemental analysis for C, H and Nwithin 0.5% of calculated value.

Step 119.14-[4-(6-Methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

A mixture of 5.0 g (16.6 mMol)4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266) and 2.52 g (18 mMol) of 6-methoxy-pyridin-3-ylmethylamine(CAS: 262295-96-5; prepared from 6-methoxy-nicotin-nitrile byhydrogenation in the presence of Raney-Nickel in methanol containingNH₃) in 3.5 ml (25 mMol) of Et₃N and 100 ml n-butanol is heated for 8 hto 140° C. Then additional 0.69 g of 6-methoxy-pyridin-3-ylmethylamineand 1.2 ml of Et₃N are added. Heating is continued for 6 h and the hotsuspension filtrated and the residue washed with n-butanol and hexane togive the title compound; m.p. 305° C.; elemental analysis for C, H and NWithin 0.5% of calculated value.

Step 119.2{4-[4-(6-Methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

5.0 g (12 mMol) of4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester in 200 ml of THF is cooled to −10° C. Then 80 ml of a 1N solution of di-isobutyl-aluminium hydride in THF are added dropwise.After stirring for 3 h at RT, 200 ml of THF and 100 ml of EtOAc areadded, followed by 10 ml of a 10%-solution of NH₄Cl in water. After 30min vigorous stirring, 20 g of Na₂SO₄ are added, then the mixture isfiltered through Celite. Concentration of the filtrate, stirring inmethanol and filtration gives the title compound; MS-ES⁺: (M+H)⁺=362.

Step 119.3(6-Methoxy-pyridin-3-ylmethyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

A suspension of 3.28 g (9.1 mMol) of{4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolin 40 ml of acetonitrile, 40 ml of dioxane and 4 ml of SOCl₂ is stirredfor 1 h at RT. The mixture is dissolved in EtOAc and NaHCO₃-solution,the aqueous layer separated off and extracted with EtOAc. The organiclayers are washed with NaHCO₃-solution, water and brine, dried (Na₂SO₄)and partially concentrated. The crystallized title compound can befiltered off; elemental analysis for C, H and N within 0.4% ofcalculated value.

Examples 120-125

The following Examples are synthesized analogously:

Exam- ple m.p. MS-ES⁺: HPLC^(a) Elem. Number Name [° C.] (M + H)⁺ t_(R)[min] anal.^(b) 120 (6-Methoxy-pyridin-3- 431 7.2 CHN ylmethyl)-{6-[4-(morpholin-4-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine121 (6-Methoxy-pyridin-3- 389 7.1 CHN ylmethyl)-{6-[4-(dimethylamino-methyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine122 (2-Methoxy-pyridin-4- 210-212 458 6.6 ylmethyl)-{6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-amine^(c) 123 (2-Methoxy-pyridin-4- 431 7.0 ylmethyl)-{6-[4-(morpholin-4-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine^(c) 124 (2-Methoxy-pyridin-4- 210-211 389 6.8CHN ylmethyl)-{6-[4- (dimethylamino-methyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-amine^(c) 125 (2-Methoxy-pyridin-4- 211-212 444 6.3CHN ylmethyl)-{6-[4- (4-methyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl}-amine^(c) ^(a)HPLC: solvent system: a):Acetonitrile + 0.05% TFA; b): water + 0.05% TFA: Grad: 20% → 100% a) inb) for 13 min + 5 min 100% a). ^(b)experimental value within 0.4% ofcalculated one ^(c)2-Methoxy-pyridin-4-ylmethylamine used [preparationsee J. Med. Chem. 36 (1993), 2362]

Examples 126-132

Cleavage of the methylether of the above compounds analogously toExample 115 gives:

Exam- ple m.p. MS-ES⁺: HPLC^(a) Elem. Number Name [° C.] (M + H)⁺ t_(R)[min] anal.^(d) 126 5-({6-[4-(4-Ethyl- 444 9.4^(b)piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)-1H-pyridin- 2-one 127 5-({6-[(4-(Dimethyl- 375 9.6^(b) CHNamino-methyl)-phenyl]- 7H-pyrrolo[2,3-d]- pyrimidin-4-ylamino}-methyl)-1H-pyridin- 2-one 128 5-({6-[4-(4-Morpholin- 417 9.7^(b) CHNylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-ylamino}-methyl)-1H-pyridin-2-one 129 4-({6-[4-(4-Ethyl- 291-292 444 9.4^(b)piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)-1H-pyridin- 2-one 130 4-({6-[4-(4-Morpholin- 417 5.7^(c) CHNylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin- 4-ylamino}-methyl)-1H-pyridin-2-one 131 4-({6-[(4-(Dimethyl- 330-332 375 5.6^(c) CHNamino-methyl)-phenyl]- 7H-pyrrolo[2,3- d]pyrimidin-4- ylamino}-methyl)-1H-pyridin-2-one 132 4-({6-[4-(4-Methyl- 5.0^(c) CHNpiperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino}-methyl)-1H-pyridin- 2-one ^(a)HPLC: solvent system: a): Acetonitrile +0.05% TFA; b): water + 0.05% TFA. ^(b)Grad: 5% → 40% a) in b) for 9min + 7 min 40% a). ^(c)Grad: 20% → 100% a) in b) for 13 min + 5 min100% a). ^(d)experimental value within 0.4% of calculated one

Example 133(2-Methoxy-pyridin-4-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

330 mg (0.90 mMol)(2-Methoxy-pyridin-4-yl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine,0.81 ml morpholine and a trace of NaI is stirred for 2 h in 20 mlboiling ethanol. A clear solution is formed from which upon cooling toRT the title compound crystallizes out and can be filtered off; TLC(CH₂Cl₂/methanol 9:1) R_(f)=0.33; MS-ES⁺: (M+H)⁺=417.

Step 133.1{4-[4-(2-Methoxy-pyridin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

To 4.16 g (16 mMol) of[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol (see Step108.3) and 1.99 g (16 mMol) of 2-methoxy-pyridin-4-ylamine [see Rec.Trav. Chim. (1955) 74, 1160; prepared from2-methoxy-4-nitro-pyridine-1-oxide by hydrogenation in the presence ofRaney-Nickel in methanol/THF] in 90 ml degassed DMF under N₂-atmosphere,996 mg of R(+)-BINAP[R(+)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthalin); 1.6 mMol], 414 mgPd₂(dba)₃.CHCl₃ [tris(dibenzylideneacetone)dipalladium (0) chloroformcomplex; 0.40 mMol] and 3.08 g (32 mMol) of sodium-tert-butylate aresubsequently added. The red solution is stirred at 70° C. over night andthen poured into a mixture of 0.5 l of EtOAc and 1 l buffer (7.8 g ofNaH₂PO₄.2H₂O, 5 g of Na₂HPO₄.2H₂O in 1 l H₂O). After stirring for 1 h,the title compound is filtered off and washed with water and EtOAc; HPLC(conditions see Examples 67-78) t_(R)=8.2 min; MS-ES⁺=348.

Step 133.2(2-Methoxy-pyridin-4-yl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

At 0° C., a suspension of 1.23 g (3.5 mMol) of{4-[4-(2-methoxy-pyridin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanolin 18 ml of acetonitrile, 18 ml of dioxane and 1.5 ml of SOCl₂ isprepared at 0° C. and then stirred for 4.5 h at RT. The mixture isdiluted with 0.2 l of EtOAc and 0.1 l of saturated NaHCO₃-solution,stirred and the title compound filtered off; MS-ES⁺: (M+H)⁺=366. Moreproduct can be obtained by extraction of the filtrate.

Examples 134-140

The following Examples are synthesized by preparing the correspondingmethoxy pyridines analogously to Example 133 followed by de-methylationto the corresponding pyridones as described in Example 115:

Exam- ple MS-ES⁺: HPLC^(a) Elem. TLC Number Name (M + H)⁺ t_(R) [min]anal.^(b) R_(f) 134 4-[6-(4-Morpholin-4- 403 7.3 0.24^(c)ylmethyl-phenyl)-7H- pyrrolo[2,3-d]pyrimidin- 4-ylamino]-1H-pyridin-2-one 135 (2-Methoxy-pyridin-4-yl)- 430 7.2 0.35^(c){6-[4-(4-methyl-piperazin- 1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl}-amine 136 4-{6-[4-(4-Methyl- 416 7.00.08^(c) piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}- 1H-pyridin-2-one 137 (2-Methoxy-pyridin-4-yl)-444 7.7 0.48^(d) {6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-amine 1384-{6-[4-(4-Ethyl-piperazin- 430 7.2 0.10^(c) 1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino}-1H-pyridin-2-one 139[6-(4-Dimethylamino- 375 7.2 CHN 0.47^(d) methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-(2-methoxy-pyridin-4- yl)-amine 1404-[6-(4-Dimethylamino- 361 7.2 0.08^(c) methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino]-1H-pyridin- 2-one ^(a)HPLC: solventsystem: a): Acetonitrile + 0.05% TFA; b): water + 0.05% TFA. Grad: 20% →100% a) in b) for 13 min + 5 min 100% a). ^(b)experimental value within0.4% of calculated one ^(c)CH₂Cl₂/MeOH/NH₃ ^(conc.) 80:20:1^(d)THF/MeOH/NH₃ ^(conc.) 90:10:0.3

Example 1416-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidine

1.56 ml of diisobutyl-aluminium hydride (1 M in THF) are added to asolution of 130 mg (0.26 mMol) of(4-ethyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanonein 13 ml of THF at −15° C. under a N₂-atmosphere. After 3 h, 4 ml ofEtOAc are added to the solution, followed by 0.2 ml of a saturatedsolution of NH₄Cl in water. After adding solid Na₂SO₄, the reactionmixture is filtered through Celite. The filtrate is concentratedtogether with 3 g of SiO₂. The resulting powder is put on top of achromatography column (SiO₂) and then eluted with EtOAc/methanol 4:1 andfinally EtOAc/methanol/NEt₃ 80:20:1, yielding the title compound; HPLC(conditions see Examples 67-78) t_(R)=10.5 min; MS-ES⁺: (M+H)⁺=485.

Step 141.14-[4-Chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

A suspension of 3.0 g (10 mMol) of4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester(WO 97/02266), 2.4 g (17 mMol) of K₂CO₃, 0.32 g (1 mMol) oftetrabutyl-ammoniumbromide and 2.0 ml (15 mMol) of4-methoxy-benzylchloride in 25 ml of 2-butanone is stirred for 18 h at80° C. Then the suspension is filtered, the residue washed with2-butanone and discarded. The filtrate is diluted with EtOAc and water,the aqueous layer separated off and extracted twice with EtOAc. Theorganic layers are washed with water and brine, dried (Na₂SO₄) andconcentrated after adding 13 g of SiO₂. The resulting powder is put ontop of a chromatography column (SiO₂) and then eluted with hexane/EtOAc2:1.4-[4-Chloro-7-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester [TLC (hexane/EtOAc 2:1) R_(f)=0.40; MS-ES⁺: (M+H)⁺=422]is eluated first, followed by the title compound; TLC (hexane/EtOAc 2:1)R_(f)=0.23; MS-ES⁺: (M+H)⁺=422.

Step 141.24-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

A mixture of 3.96 g (9.4 mMol) of4-[4-chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester, 2.14 g (13 mMol) of4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex.237) and 2.44 (17.7 mMol) of K₂CO₃ in 90 ml of DMF is heated for 9 h at95° C. The reaction mixture is concentrated in vacuuo, the residuedissolved in EtOAc and water, the aqueous layer separated off andextracted twice with EtOAc. The organic layers are washed with water andbrine, dried (Na₂SO₄) and concentrated. Column chromatography (SiO₂,EtOAc/hexane 1:1) gives the title compound; TLC (EtOAc/hexane 1:1)R_(f)=0.24; MS-ES⁺: (M+H)⁺=551.

Step 141.34-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

Hydrogenation of 0.50 g (0.91 mMol) of4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester in 150 ml of THF and 15 ml of1,3-dimethyl-2-imidazolidinone in the presence of 0.2 g of Pd/C (10%;“Engelhard 5125”), filtration and concentration gives the crude product.Stirring in THF/water, filtration and washing with water gives the titlecompound; MS-ES⁺: (M+H)⁺=431; elemental analysis for C, H, N and Fwithin 0.4% of calculated value.

Step 141.44-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid lithium salt

A suspension of 2.87 g (6.7 mMol) of4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester and 520 mg (12 mMol) LiOH.H₂O in 240 ml of dioxane and5 ml of water is stirred for 24 h at 120° C. The solid is dissolvedfirst, then a new precipitate is formed. Filtration at RT and washingwith dioxane and diethylether gives the title compound; HPLC (conditionssee Examples 67-78) t_(R)=13.5 min; MS-ES⁺: (M+H)⁺=403.

Step 141.5(4-Ethyl-piperazin-1-yl)-{4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanone

To 340 mg (0.83 mMol)4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid lithium salt in 5 ml of DMF under N₂-atmosphere, 0.38 ml (3 mMol)of N-ethylpiperazine and 0.31 ml (95%; 2 mMol) ofdiethyl-cyanphosphonate are added at 0° C. After 60 min, the suspensionis diluted with EtOAc and washed with saturated NaHCO₃-solution, waterand brine. The aqueous layers are re-extracted twice with EtOAc, theorganic layers dried (Na₂SO₄) and concentrated after adding SiO₂. Theresulting powder is put on top of a chromatography column (SiO₂) and thetitle compound eluted with EtOAc/methanol/NH₃ ^(conc.) 80:20:1; HPLC(conditions see Examples 67-78) t_(R)=10.4 min; MS-ES⁺: (M+H)⁺=499.

Examples 142-144

The following Examples are synthesized analogously to Example 141:

Ex- am- ple HPLC^(a) Num- MS-MS⁺: t_(R) Elem. m.p. TLC ber Name (M + H)⁺[min] anal.^(b) [° C.] R_(f) 142 6-[4-(4-Methyl- 471 12.8 CHNFpiperazin-1- ylmethyl)-phenyl]- 4-(4-fluoro-2- methyl-1H-indol-5-yloxy)-7H-pyrrolo- [2,3-d]pyrimidine 143 4-(4-Fluoro-2- 458 10.7 280-0.19^(c) methyl-1H-indol-5- 282 yloxy)-6-(4-mor- pholin-4-ylmethyl-phenyl)-7H-pyrrolo- [2,3-d]pyrimidine 144 {4-[4-(4-Fluoro-2- 416 10.70.21^(d) methyl-1H-indol- 5-yloxy)-7H- pyrrolo[2,3- d]pyrimidin-6-yl]-benzyl}- dimethyl-amine ^(a)HPLC: solvent system: a):Acetonitrile + 0.05% TFA; b): water + 0.05% TFA. Grad: 20% → 100% a) inb) for 13 min + 5 min 100% a). ^(b)experimental value within 0.4% ofcalculated one ^(c)EtOAc/MeOH 19:1 ^(d)EtOAc/MeOH/NEt₃ 80:20:1

Example 145((R)-1-Phenyl-ethyl)-[6-(4-piperazin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

4-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester (1.8 g, 3.5 mmol) is dissolved in 150 mL ofdioxane by gentle warming. To this solution is added a solution of 4 Nhydrochloric acid in dioxane (Aldrich, Buchs, Switzerland) (5 mL, 20mmol) and the mixture stirred at 50 to 60° C. for 1 hour. The resultingsuspension is diluted with 75 mL of methanol and stirred for 1additional hour under reflux after which the mixture is cooled and thesolvent evaporated. The residue is dissolved in diluted hydrochloricacid and washed with ethyl acetate. The aqueous phase is treated withsolid potassium carbonate until basic and evaporated. The residue whichcontains inorganic salts is purified by flash chromatography usingdichloromethane/methanol 7:3 containing 1% conc. ammonia. Pure fractionswere taken up in ethyl acetate, washed with water and brine, dried withsodium sulfate and evaporated to give the title compound as a solid;m.p. 240-242° C.; MS-ES⁺: (M+H)⁺=413; TLC R_(f)(dichloromethane/methanol7:3 containing 1% conc. ammonia) 0.35; HPLC t_(R)=6.86 min.

Example 145.14-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester

A mixture of 1.6 g (4 mmol)[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine(for the preparation see Example 9, Step 9.3 of WO 03/013541 A1) in 50ml DMF is treated with 1.56 g (8.4 mmol) N—BOC-piperazine and 2.76 g (20mmol) anhydrous potassium carbonate and the mixture heated to 65° C. for1 hour. The reaction mixture is cooled and the inorganic salts removedby filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). The DMF isevaporated under reduced pressure and the residue purified through flashchromatography using first dichloromethane/ethanol 95:5 and thendichloromethane/ethanol 9:1. The title compound is obtained as a solid;m.p. 244-246° C.; MS-ES⁺: (M+H)⁺=513; TLC R_(f)(dichloromethane/ethanol9:1) 0.46.

Example 146 Dry-Filled Capsules

5000 capsules, each comprising as active ingredient 0.25 g of one of thecompounds of formula I mentioned in the preceding Examples, are preparedas follows:

Composition active ingredient 1250 g  talcum 180 g wheat starch 120 gmagnesium stearate  80 g lactose  20 gPreparation process: The mentioned substances are pulverised and forcedthrough a sieve of 0.6 mm mesh size. 0.33 g portions of the mixture areintroduced into gelatin capsules using a capsule-filling machine.

Example 147 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula I mentioned in the precedingExamples, are prepared as follows:

Composition active ingredient 250 g PEG 400 1 liter Tween 80 1 literPreparation process: The active ingredient is pulverised and suspendedin PEG 400 (polyethylene glycol having an M_(r) of from approx. 380 toapprox. 420, Fluka, Switzerland) and Tween®80 (polyoxyethylene sorbitanmonolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland)and ground in a wet pulveriser to a particle size of approx. from 1 to 3μm. 0.43 g portions of the mixture are then introduced into soft gelatincapsules using a capsule-filling machine.

Example 148 Inhibition of the Tyrosine Kinase Activity of EGF-R (HER-1),ErbB-2 (HER-2) and VEGF Receptor (KDR)

The inhibition tests are carried out as described above. The IC₅₀ valuesfor some of the compounds of formula I are given below:

Compound from HER-1 HER-2 KDR Example No. IC₅₀ [μM] IC₅₀ [μM] IC₅₀ [μM] 3 0.0031 0.008 0.0107  4 0.0031 0.0072 0.0093  5 0.0031 0.0067 0.006  60.007 0.005 0.0127  7 0.004 0.011 0.058  8a 0.0024 0.0094 0.017 10 0.0040.009 0.0293 11 0.0043 0.005 0.0497 12 0.0047 0.005 0.1387 13 0.0060.005 0.088 14 0.0063 0.0085 0.0927 15 0.005 0.0065 0.0493  16a 0.00120.016 0.061 18 0.0165 0.0315 0.0245 43 0.005 0.0115 0.0515 48 0.00570.0075 0.058 52 0.0157 0.014 0.125 86 0.0055 0.016 0.105 94 0.0018 0.0160.042 107f  0.0025 0.045 0.019 116  0.039 0.0155 0.0155

1. A compound selected from ((R)-1-phenyl-ethyl)-[6-(4-piperazin-1-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine; 4-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-piperazine-1-carboxylic acid tert butyl ester; and pharmaceutically acceptable salts thereof.
 2. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1, together with at least one pharmaceutically acceptable carrier. 